Angiotensin: From the Kidney to Coronavirus 0323996183, 9780323996181

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Angiotensin

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Molecular Mediators in Health and Disease: How Cells Communicate

Angiotensin

From the Kidney to Coronavirus

Edited by

Paul M. Pilowsky The University of Sydney, Camperdown, NSW, Australia

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2023 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-323-99618-1 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Andre G. Wolff Editorial Project Manager: Sam Young Production Project Manager: Swapna Srinivasan Cover Designer: Matthew Limbert Typeset by TNQ Technologies

Contents List of contributors ................................................................................ xxi Preface ............................................................................................. xxxiii

CHAPTER 1 Regulation of sympathetic nerve activity by the central angiotensin system in heart failure .............. 1 Julia Shanks and Rohit Ramchandra 1 Introduction ........................................................................ 1 2 Heart failure results in an increase in resting levels of sympathetic nerve activity ..................................................... 2 2.1 Consequence of increased sympathetic nerve activity during heart failure .........................................................2 3 Role of angiotensin II ........................................................... 3 3.1 Circulating levels of angiotensin II in heart failure ...............3 3.2 Role of central angiotensinergic mechanisms.......................4 3.3 Blockade of central angiotensin type 1 receptor decreases SNA ...............................................................4 3.4 Central regions that respond to angiotensin II ......................6 4 Actions of angiotensin II within the spinal cord......................... 8 4.1 AT1R within the spinal cord..............................................8 4.2 Regulation of sympathetic nerve activity by AT1R within the spinal cord................................................................9 4.3 Changes in spinal cord AT1R during heart failure............... 11 5 Conclusions .......................................................................13 6 Future directions .................................................................13 Acknowledgments...................................................................13 References.............................................................................15

CHAPTER 2 The contribution of angiotensin peptides to cardiovascular neuroregulation in health and disease .................................................................21 Ewa Szczepanska-Sadowska, Tymoteusz Zera, Michal Kowara and Agnieszka Cudnoch-Jedrzejewska 1 Introduction......................................................................21 2 The overview of renineangiotensin system organization: cooperation of central and systemic renineangiotensin system.............................................................................21 3 Cooperation of the brain renineangiotensin system with the autonomic nervous system: interactions with the sympathetic, parasympathetic, and enteric systems....................................25

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4 Role of the brain renineangiotensin system in the regulation of watereelectrolyte balance...................................................28 4.1 Regulation of sodium and water intake........................... 28 4.2 Kidney and gastrointestinal system ................................ 29 5 Other effects of the brain renineangiotension system affecting the cardiovascular regulation: role of renine angiotension system in stress, depression, and COVID-19 ........31 5.1 Stress and depression................................................... 31 5.2 COVID-19................................................................. 32 6 Role of the brain renineangiotensin system in cardiovascular regulation in hypertension...................................................33 7 Role of brain renineangiotensin in cardiovascular regulation in heart failure ..................................................................38 8 Renineangiotension system in diabetes mellitus and metabolic syndrome...........................................................41 9 Renineangiotensin system in pathogenesis and outcome of myocardial infarction .........................................................42 9.1 Renineangiotensin system and the atherosclerotic plaque....................................................................... 42 9.2 Renineangiotensin system in outcome of myocardial infarction................................................................... 45 10 Novel therapeutic perspectives of brain targeting renineangiotensin system inhibitors in cardiovascular diseases ...........................................................................47 10.1 ACE inhibitors.......................................................... 47 10.2 Angiotensin receptor blockers ..................................... 48 11 Conclusions and perspectives ..............................................48 Acknowledgments...................................................................49 References.............................................................................50

CHAPTER 3 Renineangiotensin system and inflammation ..........77 Ana Cristina Simo˜es-e-Silva, Pedro Alves Soares Vaz de Castro, Letı´cia Bitencourt, Juliana Lacerda de Oliveira Campos, Stephanie Bruna Camilo Soares de Brito and Bruna Luisa Fischer 1 Introduction .......................................................................77 2 The classic renineangiotensin system axis ..............................79 2.1 Renin.......................................................................... 79 2.2 Angiotensin-converting enzyme....................................... 80 2.3 Angiotensin II .............................................................. 80

Contents

3 The counterregulatory renineangiotensin system axis................84 3.1 Angiotensin-converting enzyme 2.................................... 84 3.2 Angiotensin-(1e7) ........................................................ 86 3.3 Mas receptor................................................................ 86 4 Other renineangiotensin system mediators ..............................87 4.1 Alamandine ................................................................. 87 4.2 Ang-(1e9)................................................................... 88 5 Evidence in human diseases..................................................89 6 Future directions and perspectives..........................................92 References.............................................................................93

CHAPTER 4 Targeting renineangiotensin system: a strategy for drug development against neurological disorders ............................................................. 107 Bharat Bhusan Subudhi and Pratap Kumar Sahu 1 Introduction ..................................................................... 107 2 Renineangiotensin system in brain ...................................... 109 3 Drug development strategies targeting renineangiotensin system............................................................................. 113 3.1 MasR agonists............................................................ 113 4 ACE2 activators................................................................ 123 5 AT2R agonists .................................................................. 125 6 ACE inhibitors.................................................................. 128 7 AT1R blockers.................................................................. 133 8 Renin inhibitors ................................................................ 137 9 Conclusion....................................................................... 138 References........................................................................... 139

CHAPTER 5 Pharmacology of angiotensin in renovascular diseases .............................................................. 151 Kirti Gupta, Newly Bagang, Gaaminepreet Singh, Sandeep Arora, Onkar Bedi and Manish Kumar 1 Introduction ..................................................................... 151 2 RAAS in the glomerulus and tubular region: physiological and pathological considerations ........................................... 152 3 Renovascular hypertension.................................................. 155 3.1 Pathophysiology of renovascular hypertension ................. 156 3.2 Role of angiotensin II in renovascular hypertension .......... 158 3.3 AT2 receptor activation in renovascular hypertension........ 160 4 Atheromatous renovascular disease ...................................... 161 4.1 Pathophysiology of ARVD ........................................... 161

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4.2 Angiotensin II in progression of ARVD .......................... 162 4.3 Role of ACE-I/ARBs (ACE inhibitors/angiotensin receptor blockers) in ARVD ..................................................... 163 5 Ischemic renovascular disease ............................................. 164 5.1 Pathophysiology ......................................................... 165 5.2 Role of Angiotensin II in ischemia nephropathy............... 165 6 Diabetic nephropathy......................................................... 167 6.1 Pathogenesis of diabetic nephropathy ............................. 167 6.2 Role of angiotensin II, ACE inhibitors, and ARBs in diabetic nephropathy ................................................... 167 7 Conclusion....................................................................... 169 8 Conflict of interest............................................................. 170 References........................................................................... 170

CHAPTER 6 The role of angiotensins in the pathophysiology of human pregnancy............................................. 179 Kirsty G. Pringle, Eugenie R. Lumbers, Saije K. Morosin and Sarah J. Delforce 1 Introduction ..................................................................... 179 2 The renineangiotensin system............................................. 180 3 The circulating renineangiotensinealdosterone system in normal pregnancy.............................................................. 185 3.1 Changes in components of the RAAS in human pregnancy.................................................................. 185 4 The intrarenal RAS in pregnancy......................................... 187 5 The intrauterine renineangiotensin system: placenta, fetal membranes, and decidua .................................................... 190 5.1 RAS components in the placenta in normal pregnancy ...... 190 5.2 RAS components in the intrauterine membranes in normal pregnancy ....................................................... 192 5.3 RAS components in the decidua in normal pregnancy....... 193 6 The RAS and hypertension in pregnancy............................... 194 7 The role of the RAS in regulating fetal growth....................... 198 7.1 Changes in the maternal circulating RAAS in pregnancies associated with FGR ................................................... 198 7.2 Changes in placental RAS expression in pregnancies associated with FGR ................................................... 200 8 The RAS in gestational diabetes .......................................... 201 9 Conclusions ..................................................................... 203 References........................................................................... 203

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CHAPTER 7 Hematopoietic bone marrow renin-angiotensin system in health and disease ............................... 213 Umit Yavuz Malkan and Ibrahim C. Haznedaroglu 1 Introduction ..................................................................... 213 2 Local bone marrow renineangiotensin system in hematopoiesis................................................................... 215 3 Local bone marrow renineangiotensin system in neoplastic hematopoiesis................................................................... 216 4 Local bone marrow renineangiotensin system in atherosclerosis .................................................................. 217 5 Local bone marrow renineangiotensin system in hypertension..................................................................... 219 6 Local bone marrow renineangiotensin system and COVID-19 syndrome......................................................................... 220 7 Conclusion and perspectives ............................................... 225 References........................................................................... 227

CHAPTER 8 Angiotensin II as a mediator of renal fibrogenesis ......................................................... 235 Ivonne Loeffler and Gunter Wolf 1 Introduction ..................................................................... 235 2 The intrarenal renineangiotensin system............................... 235 2.1 “Classical” actions of Ang II in the kidney...................... 237 3 The renal renineangiotensin system: much more complex than previously thought...................................................... 238 3.1 Ang II and renal growth............................................... 243 3.2 Ang II and renal inflammation ...................................... 245 3.3 Ang II and renal fibrosis .............................................. 246 4 Conclusion and future directions.......................................... 251 References........................................................................... 251 Further reading..................................................................... 262

CHAPTER 9 Angiotensin and atherosclerotic vascular disease ............................................................... 263 Delia Lidia Şalaru, Cristina Adam, Dragoş Traian Marcu, Radu Andy Sascau and Cristian Statescu

1 2 3 4

The global burden of the atherosclerotic vascular disease......... 263 Endothelial dysfunction...................................................... 264 The renineangiotensin system............................................. 265 The role of angiotensin in the pathophysiology of atherosclerotic plaques ....................................................... 266

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5 Interaction between angiotensin and other mediators of the atherosclerotic process ....................................................... 270 6 Angiotensindclinical and therapeutical implications............... 275 References........................................................................... 276

CHAPTER 10 ACE2 in pulmonary diseases .............................. 285 Qing Lin and Hongpeng Jia 1 Introduction ..................................................................... 285 2 ACE2 and pulmonary hypertension ...................................... 287 3 ACE2 and asthma ............................................................. 289 4 ACE2 and pulmonary fibrosis.............................................. 290 5 ACE2 and lung cancer ....................................................... 291 6 ACE2 and chronic obstructive pulmonary disease ................... 292 7 ACE2 and acute lung injury................................................ 293 8 ACE2 and COVID-19 ........................................................ 294 9 Role of ACE2 in lung repair and regeneration........................ 296 References........................................................................... 303

CHAPTER 11 Renineangiotensinealdosterone system inhibitors. New and old approaches.................... 317 Carlos M. Ferrario, Jessica L. VonCannon, Kendra N. Wright and Sarfaraz Ahmad 1 Introduction ..................................................................... 317 2 Why new drugs for hypertension ......................................... 318 2.1 Renin........................................................................ 319 3 Perspective....................................................................... 324 Acknowledgments................................................................. 325 References........................................................................... 325

CHAPTER 12 Aspects of the intracellular renineangiotensin system............................................................... 335 Mark C. Chappell, Liliya M. Yamaleyeva, Hossam A. Shaltout and TanYa M. Gwathmey 1 Introduction ..................................................................... 335 2 Kidney ............................................................................ 336 3 Heart............................................................................... 342 4 Brain............................................................................... 343 5 Intracellular RAS ligands ................................................... 344 6 Summary......................................................................... 349 Acknowledgments................................................................. 350 References........................................................................... 350

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CHAPTER 13

Interactions between the renineangiotensine aldosterone system and COVID-19: pharmacological interventions............................ 355

Nada J. Habeichi, Ghadir Amin, Gaelle Massoud, Reine Diab, Mathias Mericskay, George W. Booz and Fouad A. Zouein 1 Introduction ..................................................................... 355 1.1 The physiology of the renineangiotensinealdosterone system ...................................................................... 355 1.2 The renineangiotensinealdosterone system and SARS-CoV-2 ............................................................. 356 2 Renineangiotensinealdosterone system therapeutic venues in the context of SARS-CoV-2 infection................................ 358 2.1 Direct renin inhibitor................................................... 358 2.2 ACEIs/ARBs.............................................................. 359 2.3 Aldosterone inhibitors (spironolactone)........................... 360 2.4 Beta-blockers ............................................................. 361 2.5 Heparin..................................................................... 362 2.6 Glucocorticoids .......................................................... 364 3 Perspectives ..................................................................... 364 Acknowledgments................................................................. 365 References........................................................................... 365

CHAPTER 14

Angiotensin II and its action within the brain during hypertension ........................................... 375

Srinivas Sriramula and Vinicia Campana Biancardi List of abbreviations.............................................................. 375 1 Introduction ..................................................................... 376 2 Hypertension and angiotensin II........................................... 377 3 Angiotensin II increases bloodebrain barrier disruption in hypertension..................................................................... 378 4 Angiotensin II, innate immune system, neuroinflammation, and hypertension............................................................... 379 4.1 AngII-induced microglia activation ................................ 379 4.2 AngII and Toll-like receptors within the central nervous system ...................................................................... 380 5 Angiotensin II and bradykinin system................................... 381 6 Future perspectives............................................................ 383 7 List of words/terms ........................................................... 384 Acknowledgments................................................................. 384 References........................................................................... 384

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CHAPTER 15 Morphological aspect of the angiotensinconverting enzyme 2 .......................................... 389 Ken Yoshimura, Yasuo Okada, Shuji Toya, Tomoichiro Asami and Shin-ichi Iwasaki 1 2 3 4

Introduction ..................................................................... 389 Overview of the RAS/RAAS cascade ................................... 390 ACE2 as a “functional receptor” during viral entry into cells.... 392 Localization of ACE2 in various tissues ................................ 393 4.1 Liver tissue................................................................ 394 4.2 Kidney tissue ............................................................. 395 4.3 Pulmonary alveoli....................................................... 396 4.4 Other tissue in the digestive system ............................... 397 5 Up- and downregulation of ACE2 and related diseases ............ 399 5.1 Two axes of RAAS cascade.......................................... 402 5.2 Expression of AT1, AT2, and MAS receptor.................... 406 5.3 Possible (down) regulation of the ACE2 after binding the SARS-CoV-2 ........................................................ 406 6 Summary......................................................................... 406 Acknowledgments................................................................. 407 References........................................................................... 407 Further reading..................................................................... 417

CHAPTER 16 The renin-angiotensin system in the eye: implications on health and disease .................... 419

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Nayara Azinheira Nobrega Cruz, Lilian Caroline Gonc¸alves de Oliveira, Mauro Silveira de Queiroz Campos, Preenie de Senanayake and Dulce Elena Casarini Introduction ..................................................................... 419 Human eye’s anatomy and physiology .................................. 421 2.1 Primary layers............................................................ 421 2.2 Visual processing........................................................ 421 2.3 Ocular barriers ........................................................... 422 2.4 Ocular blood flow regulation......................................... 422 2.5 Aqueous humor homeostasis and intraocular pressure ....... 423 Renineangiotensin system.................................................. 423 Local renineangiotensin system in the eye............................ 428 Eye diseases and the local renineangiotensin system .............. 429 5.1 Glaucoma.................................................................. 429 5.2 Diabetic retinopathy .................................................... 431

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5.3 Age-related macular degeneration.................................. 432 5.4 Retinopathy of prematurity........................................... 433 5.5 Ocular SRA and COVID-19 ......................................... 434 References........................................................................... 436

CHAPTER 17

Brain renineangiotensin system in the injured brain: the role of astrocytes and microglia ........................................................... 449

Alberto Javier Ramos 1 The renineangiotensin system and the brain renineangiotensin system............................................................................. 449 2 Astrocytes are essential homeostatic cells in the CNS that respond to brain RAS activation .......................................... 451 3 Reactive astrogliosis is a generic response to brain injury ........ 453 4 Angiotensinogen expression in reactive astrocytes .................. 454 5 AT1R and AT2R role in glial cells: the dichotomy in neuroinflammation............................................................. 455 6 Angiotensin (1e7)/MasR pathway in the control of proinflammatory reactive gliosis .......................................... 459 7 Conclusions and future directions ........................................ 460 Acknowledgments................................................................. 461 References........................................................................... 462

CHAPTER 18

Angiotensin and COVID-19.................................. 473 Gaetano Alfano

1 Introduction ..................................................................... 473 2 SARS-CoV-2.................................................................... 474 2.1 Spike (S) protein of SARS-CoV-2.................................. 474 3 ACE2.............................................................................. 475 3.1 Interaction between S protein and ACE2......................... 476 3.2 Regulation of ACE2.................................................... 477 4 Genetic polymorphisms...................................................... 478 5 Effects of SARS-CoV-2 infection......................................... 479 5.1 Respiratory system...................................................... 479 5.2 Cardiovascular system ................................................. 480 5.3 Nervous system .......................................................... 480 5.4 Urinary system........................................................... 481 5.5 Gastrointestinal system ................................................ 481 6 Perspective and future therapeutical strategy.......................... 482 7 Declaration ...................................................................... 483 References........................................................................... 483

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CHAPTER 19 Transgenic animal models for the functional analysis of ACE2 ................................................ 491 Natalia Alenina and Michael Bader 1 Introduction ..................................................................... 491 1.1 ACE2 knockout mice and rats....................................... 493 1.2 Conditional ACE2 knockout ......................................... 495 1.3 ACE2 knock-in mutation in mice .................................. 495 1.4 Cell typeespecific overexpression of ACE2 in mice ......... 496 1.5 Human ACE2 overexpression in mouse brain .................. 496 1.6 Human ACE2 overexpression in mouse heart .................. 497 1.7 Human ACE2 overexpression in mouse podocytes............ 497 1.8 Human ACE2 overexpression in rat vascular smooth muscle ...................................................................... 497 1.9 Humanized ACE2 expression in mouse/coronavirus infection models ......................................................... 497 2 Conclusions and future directions ........................................ 498 References........................................................................... 498

CHAPTER 20 Role of angiotensin in different malignancies ..... 505 Manoj Kumar Kashyap, Anjali Bhat, Divya Janjua, Rashmi Rao, Kulbhushan Thakur, Arun Chhokar, Nikita Aggarwal, Joni Yadav, Tanya Tripathi, Apoorva Chaudhary, Anna Senrung and Alok Chandra Bharti List of abbreviations.............................................................. 505 1 Introduction ..................................................................... 507 2 Renineangiotensinealdosterone system................................ 508 2.1 Primary components of RASeangiotensin pathway .......... 508 2.2 RAS components and cancer ........................................ 513 3 Clinical relevance of angiotensins in different cancers ............. 514 3.1 Cervical cancer......................................................... 521 3.2 Prostate cancer ......................................................... 521 3.3 Esophageal cancers and Barrett’s esophagus .................. 522 3.4 Ovarian cancer.......................................................... 523 3.5 Hepatocellular carcinoma ........................................... 523 3.6 Breast cancer............................................................ 525 3.7 Pancreatic cancer ...................................................... 526 3.8 Lung cancer ............................................................. 526 3.9 Gastric cancer........................................................... 528 3.10 Colorectal cancer ...................................................... 529

Contents

4 Angiotensin receptor inhibition and reprogramming of tumor microenvironment ............................................................. 529 5 Inhibition of RAS components and impact on cancer progression ...................................................................... 530 6 Challenges associated with angiotensin inhibitors ................... 530 7 Perspectives ..................................................................... 531 Acknowledgments................................................................. 532 References........................................................................... 532

CHAPTER 21

ACE2/angiotensin-(1e7)/mas receptor axis in the central nervous system: physiology and pathophysiology ................................................. 545 E.C. Brito-Toscano, N.P. Rocha, M.A. Rachid, A.L. Teixeira and A.S. de Miranda

1 Introduction ..................................................................... 545 2 ACE2/Ang-(1e7)/mas receptor axis in central nervous system physiology ....................................................................... 546 3 ACE2/Ang-(1e7)/mas receptor axis in central nervous system pathophysiology................................................................ 547 3.1 ACE2/Ang-(1e7)/mas receptors role in neurodegenerative disorders ................................................................... 547 3.2 ACE2/Ang-(1e7)/mas receptors role in mood disorders .... 551 3.3 ACE2/Ang-(1e7)/mas receptors role in cerebrovascular diseases..................................................................... 552 4 Concluding remarks........................................................... 557 Acknowledgments................................................................. 558 References........................................................................... 558

CHAPTER 22

The therapeutic potential of angiotensin-(1e7)... 567 Ana Clara Melo, E. Ann Tallant and Patricia E. Gallagher

1 2 3 4

Introduction ..................................................................... 567 Angiotensin-(1e7)/Mas1 receptor axis.................................. 567 Ang-(1e7)/Mas1 axisda target for cancer drug development... 570 Preclinical research ........................................................... 573 4.1 In vitro studies ........................................................... 573 4.2 Animal models........................................................... 576 4.3 Ang-(1e7)dcombination therapy.................................. 580 5 Clinical research ............................................................... 581 5.1 Clinical trials in cancer patients administered Ang-(1e7) .. 582 5.2 Ang-(1e7) with standard-of-care chemotherapy............... 583

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6 Future directions ............................................................... 584 6.1 Limitations of Ang-(1e7) as a drug ............................... 585 6.2 Analogs of Ang-(1e7) with anticancer properties............. 585 7 Conclusions ..................................................................... 588 Acknowledgments................................................................. 588 References........................................................................... 588

CHAPTER 23 Angiotensin and pain ......................................... 597 Cristian G. Acosta, Sean I. Patterson, Susana R. Valdez and Alicia M. Seltzer 1 Introduction ..................................................................... 597 1.1 The renineangiotensin system ...................................... 597 1.2 Basics on pain............................................................ 600 1.3 Brief introduction to the roles of angiotensin in the context of pain ........................................................... 601 2 Role of angiotensin and its major receptors (and associated signaling molecules) in pain................................................ 602 2.1 Angiotensin in nocifensive pain..................................... 602 2.2 Angiotensin and neuropathic (pathological) pain.......................................................................... 603 2.3 Angiotensin and inflammatory pain................................ 605 2.4 Angiotensin and cancer pain......................................... 606 2.5 Angiotensin and muscle pain ........................................ 608 2.6 Angiotensin and fibromyalgia ....................................... 609 2.7 Angiotensin and sickle celleassociated pain.................... 610 3 Outside the box: a link between RAS, thyroid hormones, and pain?......................................................................... 610 4 COVID-19, RAS, thyroid status, and pain ............................. 613 5 Concluding remarks........................................................... 615 References........................................................................... 615 Further reading..................................................................... 622

CHAPTER 24 The renin-angiotensin system, emotional stress and anxiety .............................................. 623 Marco Antoˆnio Peliky Fontes, Lucas M. Kangussu and Ana Cristina Simo˜es-e-Silva 1 Renineangiotensin system and emotional stress: general aspects ................................................................. 623 1.1 Emotional stress and anxiety disorders: need for new therapeutic strategies ................................................... 623

Contents

1.2 Contemporary renineangiotensin system: far more complex than initially proposed..................................... 624 1.3 The renineangiotensin system: from vascular effects to behavioral modulation ................................................. 625 2 RAS components as therapeutical targets for stress-associated conditions: potential strategies............................................. 626 2.1 Blockade of classical axis: ACE/angiotensin II/AT1 receptors ................................................................... 626 2.2 Activation of ACE2/angiotensin-(1e7)/Mas receptor axis .......................................................................... 628 3 Clinical evidence: should doctors prescribe AT1 receptor blockers and ACE inhibitors for stress-associated conditions?....................................................................... 629 4 Conclusions ..................................................................... 632 Acknowledgments................................................................. 632 References........................................................................... 633

CHAPTER 25

Angiotensins in obesity: focus on white adipose tissue ................................................... 641

Beatriz Alexandre-Santos, Vinı´cius Sepu´lveda-Fragoso, D’Angelo Carlo Magliano and Eliete Dalla Corte Frantz List of abbreviations.............................................................. 641 1 Introduction ..................................................................... 642 2 Ang II: main functions in WAT ........................................... 644 2.1 Lipid storage.............................................................. 645 2.2 Adipogenesis ............................................................. 645 2.3 Inflammation.............................................................. 647 2.4 Glucose metabolism .................................................... 648 2.5 Browning .................................................................. 648 3 Ang (1e7): main functions in WAT...................................... 650 3.1 Lipid storage.............................................................. 650 3.2 Adipogenesis ............................................................. 652 3.3 Inflammation.............................................................. 652 3.4 Glucose metabolism .................................................... 652 3.5 Browning .................................................................. 653 4 Additional angiotensins...................................................... 654 4.1 Ang III or Ang (2e8) .................................................. 654 4.2 Ang IV or Ang (3e8) .................................................. 656 4.3 Alamandine ............................................................... 657 4.4 Final remarks............................................................. 657 References........................................................................... 658

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CHAPTER 26 Angiotensin in the gut: roles in inflammatory bowel disease.................................................... 669 Yan Chun Li 1 2 3 4

Introduction ..................................................................... 669 The renineangiotensin system............................................. 669 Local renineangiotensin system in the intestine ..................... 671 The renineangiotensin system and inflammatory bowel disease ............................................................................ 672 5 Perspectives ..................................................................... 675 Acknowledgments................................................................. 675 References........................................................................... 675

CHAPTER 27 The renineangiotensin system in gastrointestinal functions ................................... 681 Maria Grazia Zizzo and Rosa Serio 1 Introduction ..................................................................... 681 2 RAS and gut motility......................................................... 682 2.1 Upper gastrointestinal tract: esophagus, lower esophageal sphincter, and stomach................................................. 683 2.2 Small intestine ........................................................... 684 2.3 Large intestine ........................................................... 686 3 RAS and epithelial functions............................................... 688 3.1 Upper gastrointestinal tract: esophagus and stomach ......... 689 3.2 Small intestine ........................................................... 690 3.3 Large intestine ........................................................... 692 4 Summary and conclusions .................................................. 693 References........................................................................... 694

CHAPTER 28 Angiotensin in shock: experimental and clinical studies .................................................. 699 Emily J. See, Yugeesh R. Lankadeva, Rinaldo Bellomo and Clive N. May 1 Background...................................................................... 699 2 Experimental studies.......................................................... 700 2.1 Sepsis ....................................................................... 700 2.2 Ovine model of sepsis ................................................. 700 2.3 Angiotensin II in early experimental sepsis ..................... 701 2.4 Renal bioenergetics ..................................................... 703 2.5 Intrarenal perfusion and oxygenation in sepsis ................. 703 2.6 Effects of Ang II on intrarenal perfusion and PO2 in established sepsis........................................................ 704

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3 Clinical studies ................................................................. 707 3.1 Angiotensin II, an emerging vasopressor for use in sepsis........................................................................ 707 3.2 Ang II treatment for COVID-19 .................................... 711 3.3 Angiotensin II treatment for postoperative hypotension ..... 711 3.4 Safety of angiotensin II................................................ 712 3.5 Cost-effectiveness ....................................................... 712 3.6 Angiotensin I/II ratio and renin ..................................... 712 3.7 Future directions......................................................... 713 References........................................................................... 713

CHAPTER 29

Angiotensin II and astrocytes relevance in mental disorders ................................................ 717 Occhieppo Victoria Bele´n, Basmadjian Osvaldo Martı´n, Marchese Natalia Andrea, Baiardi Gustavo and Bregonzio Claudia

1 Introduction ..................................................................... 717 2 Astrocytes in dopamine-related mental disorders .................... 718 2.1 Parkinson’s disease ..................................................... 719 2.2 Major depression ........................................................ 719 2.3 Schizophrenia ............................................................ 720 3 AT1-R in dopamine imbalance: our first evidence ................... 720 3.1 Astrocytes in ketamine-induced dopamineeglutamate imbalance model ........................................................ 720 3.2 Study of AT1-R involvement in long-lasting ketamine effects in the dorsal striatum......................................... 722 4 Final considerations........................................................... 726 References........................................................................... 727

CHAPTER 30 1 2 3 4 5 6 7 8

Angiotensin II and polycystic kidney disease ...... 733

Sheran Li, Shabarni Gupta and Jacqueline Kathleen Phillips Introduction ..................................................................... 733 Evidence of RAS dysregulation in PKD................................ 734 Ang II cross-talk with cystogenic pathways ........................... 736 The role of Ang II in abnormal water and salt handling in PKD............................................................................ 738 The role of Ang II in extrarenal disease in PKD..................... 739 ACE inhibitors/ARBs in clinical trials .................................. 739 Conclusion....................................................................... 741 Disclosure........................................................................ 741

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Acknowledgments................................................................. 741 References........................................................................... 742

CHAPTER 31 The role of angiotensin peptides in the brain during health and disease .................................. 749 David E. Wong Zhang, Christopher G. Sobey and T. Michael De Silva 1 Introduction ..................................................................... 749 1.1 The formation of angiotensin peptides............................ 749 1.2 Angiotensin receptors .................................................. 752 1.3 Angiotensin and the regulation of neurovascular structure and function............................................................... 752 2 Angiotensin in the development of cognitive impairment ......... 754 2.1 Hypertension.............................................................. 754 2.2 Stroke....................................................................... 755 3 The role of angiotensin in the brain: contributions to memory, learning, and cognitive impairment....................................... 756 3.1 Memory and learning .................................................. 756 3.2 Cognitive impairment and dementia............................... 758 4 Modulation of the RAAS as a therapy for cognitive impairment and dementia ................................................... 759 4.1 ACE inhibitors ........................................................... 759 4.2 AT1R antagonists........................................................ 760 4.3 AT2R agonists............................................................ 760 4.4 The ACE2/angiotensin (1e7)/MasR axis......................... 761 4.5 Angiotensin IV and AT4R agonist.................................. 761 4.6 Other components of the RAAS .................................... 762 5 Conclusion....................................................................... 762 References........................................................................... 763 Index...................................................................................................775

List of contributors Cristian G. Acosta Laboratory of Studies in Neurobiology (LABENE), IHEM-CONICET, National University of Cuyo, Mendoza, Argentina; Institute of Physiology, National University of Cuyo, Medical School, Mendoza, Argentina Cristina Adam Institute of Cardiovascular Diseases Prof. Dr. George I.M.Georgescu, Iasi, Romania Nikita Aggarwal Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India Sarfaraz Ahmad Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, United States Natalia Alenina Max-Delbru¨ck-Center for Molecular Medicine (MDC), Berlin, Germany; DZHK (German Center for Cardiovascular Research), Berlin, Germany Beatriz Alexandre-Santos Department of Morphology, Laboratory of Exercise Sciences, Biomedical Institute, Fluminense Federal University, Niteroi, RJ, Brazil; Research Center on Morphology and Metabolism, Biomedical Institute, Fluminense Federal University, Niteroi, RJ, Brazil Gaetano Alfano Nephrology Dialysis and Transplant Unit, University Hospital of Modena, Modena, Italy Ghadir Amin Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon; The Cardiovascular, Renal, and Metabolic Diseases Research Center of Excellence, American University of Beirut Medical Center, Beirut, Lebanon Sandeep Arora Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India Tomoichiro Asami Speech-Language-Hearing Therapy, Faculty of Rehabilitation, Gunma Paz University, Takasaki Tonya-machi, Takasaki, Gunma, Japan Nayara Azinheira Nobrega Cruz Nephrology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil

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Michael Bader Max-Delbru¨ck-Center for Molecular Medicine (MDC), Berlin, Germany; DZHK (German Center for Cardiovascular Research), Berlin, Germany; Charite´ e University Medicine, Berlin, Germany; Institute for Biology, University of Lu¨beck, Lu¨beck, Germany Newly Bagang Department of Pharmacology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India Onkar Bedi Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India Rinaldo Bellomo Intensive Care Unit, Austin Hospital, Melbourne, VIC, Australia; Department of Critical Care, University of Melbourne, Melbourne, VIC, Australia Anjali Bhat Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India Vinicia Campana Biancardi Anatomy, Physiology and Pharmacology Department, College of Veterinary Medicine, Auburn University, Auburn, AL, United States; Center for Neuroscience Initiative, Auburn University, Auburn, AL, United States Letı´cia Bitencourt Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil George W. Booz Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center, Jackson, MS, United States E.C. Brito-Toscano Laborato´rio Integrado de Pesquisas em Patologia, Faculdade de Medicina, Universidade Federal de Juiz de Fora (UFJF), Juiz de Fora, MG, Brazil; Laborato´rio de Fisiopatologia no Envelhecimento, Faculdade de Medicina, Universidade de Sa˜o Paulo (USP), Sa˜o Paulo, SP, Brazil D’Angelo Carlo Magliano Research Center on Morphology and Metabolism, Biomedical Institute, Fluminense Federal University, Niteroi, RJ, Brazil Lilian Caroline Gonc¸alves de Oliveira Nephrology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil

List of contributors

Alok Chandra Bharti Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India Mark C. Chappell Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, United States Apoorva Chaudhary Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India Arun Chhokar Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India Bregonzio Claudia IFEC-CONICET, Departamento de Farmacologı´a, Universidad Nacional de Co´rdoba, Co´rdoba, Argentina Eliete Dalla Corte Frantz Department of Morphology, Laboratory of Exercise Sciences, Biomedical Institute, Fluminense Federal University, Niteroi, RJ, Brazil; Research Center on Morphology and Metabolism, Biomedical Institute, Fluminense Federal University, Niteroi, RJ, Brazil; National Institute for Science & Technology - INCT Physical (In)activity & Exercise, Niteroi, RJ, Brazil Agnieszka Cudnoch-Jedrzejewska Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland Sarah J. Delforce School of Biomedical Sciences & Pharmacy, College of Health, Medicine & Wellbeing, University of Newcastle, Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia A.S. de Miranda Laborato´rio de Neurobiologia, Departamento de Morfologia, Instituto de Cieˆncias Biolo´gicas, UFMG, Belo Horizonte, MG, Brazil; Laborato´rio Interdisciplinar de Investigac¸a˜o Me´dica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil Juliana Lacerda de Oliveira Campos Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil

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Preenie de Senanayake Cole Eye Institute, Cleveland Clinic, Cleveland, OH, United States T. Michael De Silva Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia Reine Diab Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon; The Cardiovascular, Renal, and Metabolic Diseases Research Center of Excellence, American University of Beirut Medical Center, Beirut, Lebanon Dulce Elena Casarini Nephrology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil Carlos M. Ferrario Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, United States Bruna Luisa Fischer Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil Patricia E. Gallagher Hypertension and Vascular Research, Department of Surgical Sciences, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, United States Kirti Gupta MM College of Pharmacy, Maharishi Markandeshwar Deemed to Be University, Mullana, Ambala (Haryana), India Shabarni Gupta Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia Baiardi Gustavo IFEC-CONICET, Departamento de Farmacologı´a, Universidad Nacional de Co´rdoba, Co´rdoba, Argentina TanYa M. Gwathmey Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, United States

List of contributors

Nada J. Habeichi Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon; The Cardiovascular, Renal, and Metabolic Diseases Research Center of Excellence, American University of Beirut Medical Center, Beirut, Lebanon; Department of Signaling and Cardiovascular Pathophysiology, Universite´ Paris-Saclay, Inserm, Chaˆtenay-Malabry, France Ibrahim C. Haznedaroglu Department of Hematology, Hacettepe University School of Medicine, Ankara, Turkey Shin-ichi Iwasaki The Nippon Dental University, Chiyoda-Ku, Tokyo, Japan; Gumna Paz University, Takasaki City, Gunma, Japan Divya Janjua Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India Hongpeng Jia Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland Lucas M. Kangussu Translational Biology Laboratory, Department of Morphology, Biological Sciences Institute, Federal University of Minas Gerais (UFMG), Brazil Manoj Kumar Kashyap Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India; Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Panchgaon (Manesar), Gurugram, Haryana, India Jacqueline Kathleen Phillips Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia Michal Kowara Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland Manish Kumar Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India Yugeesh R. Lankadeva Preclinical Critical Care Unit, Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia; Department of Critical Care, University of Melbourne, Melbourne, VIC, Australia

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Sheran Li Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia; Department of Emergency Medicine, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China Yan Chun Li Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, United States Qing Lin Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland Ivonne Loeffler Department of Internal Medicine III, Jena University Hospital-Friedrich Schiller University, Jena, Germany Eugenie R. Lumbers School of Biomedical Sciences & Pharmacy, College of Health, Medicine & Wellbeing, University of Newcastle, Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia Umit Yavuz Malkan Department of Hematology, Hacettepe University School of Medicine, Ankara, Turkey Dragoş Traian Marcu University of Medicine and Pharmacy Grigore T.Popa, Iasi, Romania Gaelle Massoud Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon; The Cardiovascular, Renal, and Metabolic Diseases Research Center of Excellence, American University of Beirut Medical Center, Beirut, Lebanon Clive N. May Preclinical Critical Care Unit, Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia; Department of Critical Care, University of Melbourne, Melbourne, VIC, Australia Ana Clara Melo Hypertension and Vascular Research, Department of Surgical Sciences, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, United States Mathias Mericskay Department of Signaling and Cardiovascular Pathophysiology, Universite´ ParisSaclay, Inserm, Chaˆtenay-Malabry, France

List of contributors

Saije K. Morosin School of Biomedical Sciences & Pharmacy, College of Health, Medicine & Wellbeing, University of Newcastle, Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia Marchese Natalia Andrea IFEC-CONICET, Departamento de Farmacologı´a, Universidad Nacional de Co´rdoba, Co´rdoba, Argentina Yasuo Okada Department of Pathology, School of Life Dentistry at Niigata, The Nippon Dental University, Niigata, Japan Basmadjian Osvaldo Martı´n IFEC-CONICET, Departamento de Farmacologı´a, Universidad Nacional de Co´rdoba, Co´rdoba, Argentina Sean I. Patterson Laboratory of Studies in Neurobiology (LABENE), IHEM-CONICET, National University of Cuyo, Mendoza, Argentina; Institute of Physiology, National University of Cuyo, Medical School, Mendoza, Argentina Marco Antoˆnio Peliky Fontes Hypertension Laboratory, Department of Physiology & Biophysics, Biological Sciences Institute, Federal University of Minas Gerais (UFMG), Brazil Kirsty G. Pringle School of Biomedical Sciences & Pharmacy, College of Health, Medicine & Wellbeing, University of Newcastle, Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia M.A. Rachid Laborato´rio de Patologia Celular e Molecular, Departamento de Patologia Geral, Instituto de Cieˆncias Biolo´gicas, UFMG, Belo Horizonte, MG, Brazil Rohit Ramchandra Manaaki Manawa - The Centre for Heart Research and the Department of Physiology, The University of Auckland, Faculty of Medical and Health Sciences, Auckland, New Zealand Alberto Javier Ramos Laboratorio de Neuropatologı´a Molecular, Instituto de Biologı´a Celular y Neurociencia “Prof. E. De Robertis” UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Medicina, Primera Unidad Acade´mica de Histologı´a, Embriologı´a, Biologı´a Celular y Gene´tica, Ciudad de Buenos Aires, Argentina

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Rashmi Rao School of Life Sciences & Allied Health Sciences, The Glocal University, Saharanpur, Uttar Pradesh, India N.P. Rocha The Mitchell Center for Alzheimer’s disease and Related Brain Disorders, Department of Neurology, the University of Texas Health Science Center, Houston, TX, United States; HDSA Center of Excellence at University of Texas Health Science Center at Houston, Houston, TX, United States; Neuropsychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas, Houston, TX, United States Pratap Kumar Sahu Department of Pharmacology, School of Pharmaceutical Sciences, Siksha O Anusandhan Deemed to Be University, Bhubaneswar, Odisha, India Radu Andy Sasc au Institute of Cardiovascular Diseases Prof. Dr. George I.M.Georgescu, Iasi, Romania; University of Medicine and Pharmacy Grigore T.Popa, Iasi, Romania Emily J. See Intensive Care Unit, Austin Hospital, Melbourne, VIC, Australia; Department of Critical Care, University of Melbourne, Melbourne, VIC, Australia Alicia M. Seltzer Laboratory of Studies in Neurobiology (LABENE), IHEM-CONICET, National University of Cuyo, Mendoza, Argentina Anna Senrung Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India Vinı´cius Sepu´lveda-Fragoso Research Center on Morphology and Metabolism, Biomedical Institute, Fluminense Federal University, Niteroi, RJ, Brazil Rosa Serio Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy Hossam A. Shaltout Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, United States; Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, NC, United States

List of contributors

Julia Shanks Manaaki Manawa - The Centre for Heart Research and the Department of Physiology, The University of Auckland, Faculty of Medical and Health Sciences, Auckland, New Zealand Mauro Silveira de Queiroz Campos Ophthalmology Division, Escola Paulista de Medicina, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil Ana Cristina Simo˜es-e-Silva Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil Gaaminepreet Singh Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India Stephanie Bruna Camilo Soares de Brito Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil Christopher G. Sobey Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia Srinivas Sriramula Department of Pharmacology and Toxicology, Brody School of Medicine at East Carolina University, Greenville, NC, United States Cristian St atescu Institute of Cardiovascular Diseases Prof. Dr. George I.M.Georgescu, Iasi, Romania; University of Medicine and Pharmacy Grigore T.Popa, Iasi, Romania Bharat Bhusan Subudhi Drug Development and Analysis Laboratory, School of Pharmaceutical Sciences, Siksha O Anusandhan Deemed to Be University, Bhubaneswar, Odisha, India Ewa Szczepanska-Sadowska Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland Delia Lidia Şalaru Institute of Cardiovascular Diseases Prof. Dr. George I.M.Georgescu, Iasi, Romania; University of Medicine and Pharmacy Grigore T.Popa, Iasi, Romania

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E. Ann Tallant Hypertension and Vascular Research, Department of Surgical Sciences, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, United States A.L. Teixeira Neuropsychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States; Instituto de Ensino e Pesquisa, Faculdade Santa Casa BH, Belo Horizonte, MG, Brazil Kulbhushan Thakur Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India Shuji Toya Oral and Maxillofacial Surgery, The Nippon Dental University Niigata Hospital, Niigata, Japan Tanya Tripathi Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India Susana R. Valdez Laboratory of Reproduction and Lactation, IMBECU-CONICET, National University of Cuyo, Mendoza, Argentina; Faculty of Exact and Natural Sciences, National University of Cuyo, Mendoza, Argentina Pedro Alves Soares Vaz de Castro Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil Occhieppo Victoria Bele´n IFEC-CONICET, Departamento de Farmacologı´a, Universidad Nacional de Co´rdoba, Co´rdoba, Argentina Jessica L. VonCannon Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, United States Gunter Wolf Department of Internal Medicine III, Jena University Hospital-Friedrich Schiller University, Jena, Germany David E. Wong Zhang Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia

List of contributors

Kendra N. Wright Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, United States Joni Yadav Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India Liliya M. Yamaleyeva Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, United States Ken Yoshimura Department of Dental Hygiene, The Nippon Dental University College at Niigata, Niigata, Japan Tymoteusz Zera Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland Maria Grazia Zizzo Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy; ATeN (Advanced Technologies Network) Center, University of Palermo, Palermo, Italy Fouad A. Zouein Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon; The Cardiovascular, Renal, and Metabolic Diseases Research Center of Excellence, American University of Beirut Medical Center, Beirut, Lebanon; Department of Signaling and Cardiovascular Pathophysiology, Universite´ Paris-Saclay, Inserm, Chaˆtenay-Malabry, France; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center, Jackson, MS, United States

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Preface Paul M. Pilowsky University of Sydney, Camperdown, NSW, Australia

This volume addresses the distribution and physiological functions of angiotensin peptides and related proteins, the potential for therapeutic agents to interact with the angiotensin system, and the importance of angiotensin system in relation to COVID19. In late September 1939, IH Page and OM Helmer, working at the Indianapolis City Hospital, submitted a manuscript on the hypertensive effects of a substance produced by the action of renin on a substrate found in plasma: “For this substance we suggest the name “angiotonin” [Greek aggεion, blood vessel, þ sono2 (sεinu), strain]” [1e3]. At that time, it was not known that angiotensin was a peptide, although the idea that its precursor was present in blood was well understood. In the years that followed, the physiology of angiotensin and its relationship to the development of hypertension was clarified [4]. If the blood flow to the kidney is reduced, prorenin is released and converted to the active enzyme renin [5]. Renin acts on the liver protein angiotensinogen to produce angiotensin I, a key precursor peptide. Within the lungs, high concentrations of the enzyme ACE (angiotensinconverting enzyme) generate angiotensin II, which then passes into the circulation where it has many effects including vasoconstriction (by acting on smooth muscle type 1 angiotensin II receptors: AT1R) [6] and thirst (by acting at circumventricular organs in the brain) release of aldosterone from the adrenal cortex (leading to sodium and water retention) [7]. Angiotensin II also has profound effects on blood pressure regulation within the central nervous system [8] and on sympathetic neurons in the spinal cord [9]. In the decades that followed, it became clear that the angiotensin and aldosterone systems are critical in the control of fluid and electrolyte balance generally, and the long-term control of arterial blood pressure. Upregulation of the AT1R is present in hypertension [10] and, with recognition of the importance of the RAAS (renineangiotensinealdosterone system), development of drugs that blocked formation of angiotensin or the AT1R were introduced to great effect as pharmacological tools to manage human hypertension likely including the hypertension that is associated with intermittent hypoxia and obstructive sleep apnea [6]. The finding that functional renineangiotensin systems exist locally within tissues further highlighted the importance of this system. A second critical breakthrough occurred with the discovery that angiotensin [1e7], another peptide product of the angiotensin precursor, could be produced by a second angiotensin-converting enzyme (ACE2) that is also distributed

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throughout the body [11]. The actions of angiotensin [1e7] are generally opposite to those of angiotensin II. ACE2 is also a critical receptor for coronaviruses. ACE2 is commonly found as a membrane-bound protein and is the protein that coronaviruses bind to in order to gain access to cells. The ACE2-binding spike protein is present on all coronaviruses that cause disease in humans including the virus responsible for COVID19 [12].

References [1] Page IH. On the nature of the pressor action of renin. J Exp Med 1939;70(5):521e42. [2] Page IH, Helmer OM. A crystalline pressor substance (angiotonin) resulting from the reaction between renin and renin-activator. J Exp Med 1940;71(1):29e42. [3] Page IH, Helmer OM, Plentl AA, Kohlstaedt KG, Corcoran AC. Suggested change in designation of “renin-activator” (hypertensinogen) to renin-substrate (a globulin). Science 1943;98(2537):153e4. [4] Johnston CI. Biochemistry and pharmacology of the renin-angiotensin system. Drugs 1990;39(1):21e31. [5] Johnston CI, Matthews PG, Davis JM, Morgan T. Renin measurement in blood collected from the efferent arteriole of the kidney of the rat. Pflugers Arch 1975;356(3):277e86. [6] Kim SJ, Fong AY, Pilowsky PM, Abbott SBG. Sympathoexcitation following intermittent hypoxia in rat is mediated by circulating angiotensin II acting at the carotid body and subfornical organ. J Physiol 2018;596(15):3217e32. [7] Mazzocchi G, Gottardo G, Macchi V, Malendowicz LK, Nussdorfer GG. The AT2 receptor-mediated stimulation of adrenal catecholamine release may potentiate the AT1 receptor-mediated aldosterone secretagogue action of angiotensin-II in rats. Endocr Res 1998;24(1):17e28. [8] McMullan S, Goodchild AK, Pilowsky PM. Circulating angiotensin II attenuates the sympathetic baroreflex by reducing the barosensitivity of medullary cardiovascular neurones in the rat. J Physiol 2007;582(Pt 2):711e22. [9] Oshima N, Kumagai H, Onimaru H, Kawai A, Pilowsky PM, Iigaya K, et al. Monosynaptic excitatory connection from the rostral ventrolateral medulla to sympathetic preganglionic neurons revealed by simultaneous recordings. Hypertens Res 2008;31(7): 1445e54. [10] Reja V, Goodchild AK, Phillips JK, Pilowsky PM. Upregulation of angiotensin AT1 receptor and intracellular kinase gene expression in hypertensive rats. Clin Exp Pharmacol Physiol 2006;33(8):690e5. [11] Burrell LM, Johnston CI, Tikellis C, Cooper ME. ACE2, a new regulator of the reninangiotensin system. Trends Endocrinol Metab 2004;15(4):166e9. [12] Li W, Moore MJ, Vasllieva N, Sui J, Wong SK, Berne MA, et al. Angiotensinconverting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003; 426(6965):450e4.

CHAPTER

Regulation of sympathetic nerve activity by the central angiotensin system in heart failure

1

Julia Shanks, Rohit Ramchandra Manaaki Manawa - The Centre for Heart Research and the Department of Physiology, The University of Auckland, Faculty of Medical and Health Sciences, Auckland, New Zealand

1. Introduction Heart failure (HF) is a major public health epidemic that is increasingly prevalent in developed countries and is the leading cause of hospital admission for those over 65 years of age. An estimated 5.7 million Americans have HF, and it is predicted that a further 3 million will have HF by 2030 [1]. Despite advances in new treatments and therapies, HF patients continue to have a high mortality and morbidity burden. The Framingham Study reported that 59% of men and 45% of women with HF would die within 5 years of diagnosis [2]. This 5-year mortality rate is worse than most cancers [3]. The increasing incidence of HF is due to the aging of the population, an increase in the prevalence of risk factors such as obesity and diabetes, and a decrease in fatality associated with improved treatment of acute coronary syndromes. A hallmark of HF is the activation of many neurohumoral systems, such as the renineangiotensinealdosterone system and the sympathetic nervous system [4,5], in response to decreased cardiac output and subsequent underperfusion of tissues. Although these compensatory mechanisms are beneficial in the short term, chronic activation of these systems leads to further deterioration and contributes to a worse prognosis. Thus, the sympathetic nervous system and the renineangiotensin system remain current therapeutic targets [4,5]. It is important to note that the sympathetic nervous system appears to be activated in both HF with reduced ejection fraction and HF with preserved ejection fraction [6]. This is relevant since HF with preserved ejection fraction is estimated to include around 50% of the patients with clinical features of HF. This chapter will focus specifically on the actions of angiotensin II within the brain and spinal cord in modulation of sympathetic nerve activity (SNA) in HF.

Angiotensin. https://doi.org/10.1016/B978-0-323-99618-1.00020-9 Copyright © 2023 Elsevier Inc. All rights reserved.

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CHAPTER 1 Regulation of sympathetic nerve activity

2. Heart failure results in an increase in resting levels of sympathetic nerve activity While activation of the sympathetic nervous system is a hallmark feature of HF, it is important to note that there are differential changes to individual organs, in both the extent of the increase and the timeline of when SNA increases. In a seminal study in 1986, cardiac norepinephrine spillover in patients with severe HF was elevated up to 50-fold, whereas that from the kidney was only increased 3-fold, and that from the lungs, gut, and liver was unchanged [7]. These findings reiterate that SNA is differentially regulated and implicates distinct mechanisms in mediating the increased SNA to individual organs during HF. A further important finding was that cardiac spillover of norepinephrine occurred before that to the kidney and other organs [8]. These results indicate that the heart is not only exposed to higher levels of norepinephrine release than other organs but for longer. These findings led to the first trial demonstrating the lifesaving properties of a b-adrenergic blocker in HF [9], leading to the current widespread use of b-blockers as a primary therapy in HF. In addition to norepinephrine spillover studies in patients with HF, there is also good evidence in preclinical animal models of HF. Direct recordings of SNA have predominantly focused on the heart and the kidney. In a large animal model of ventricular pacing-induced HF, a significant increase in directly recorded cardiac SNA was observed [10,11], indicating the increase in cardiac spillover of norepinephrine in patients with HF is mediated by both an increase in SNA and a decrease in reuptake [8]. In normal healthy animals, the resting levels of cardiac SNA were set much lower than that of renal SNA, indicating differential central control of these sympathetic outflows under normal physiological conditions [12]. In terms of the timeline of activation, norepinephrine spillover from the heart increases approximately threefold in patients with mild to moderate HF (NYHA II, IIIA, ejection fraction ¼ 29  7%). However, there is no change in spillover from the kidney at this stage. This result is in agreement with findings from the preclinical large animal model. Renal norepinephrine spillover increases in patients with severe HF (NYHA IIIB, IV, ejection fraction ¼ 18  5%) and is accompanied by a further increase of spillover of norepinephrine from the heart [8]. In both rat and rabbit models of HF, where either ligation or pacing induces HF, there is a consistent, reproducible increase in renal SNA [13e17]. These results establish that the increase in renal norepinephrine spillover observed in patients with HF is due to an increase in directly recorded renal SNA.

2.1 Consequence of increased sympathetic nerve activity during heart failure The sustained high levels of SNA have numerous deleterious consequences that play an important contributing role to the poor prognosis of patients with HF. The increase in spillover of norepinephrine to the heart and kidney accounts for 62% of

3. Role of angiotensin II

the increase in total plasma norepinephrine spillover in patients with HF [7]. The importance of these increases in SNA to the heart and kidney in HF is emphasized by the finding that increases in the sympathetic drive to both of these organs are associated with reduced survival [18,19]. Increased sympathetic drive to the heart increases the levels of norepinephrine released, which causes downregulation of cardiac b-adrenoceptors, and the released norepinephrine has toxic effects on sympathetic nerve terminals [20]. Excess norepinephrine release also induces left ventricular fibrosis and hypertrophy [21] and promotes the development of arrhythmias and sudden death [18]. While there is downregulation of cardiac b-adrenoceptors, there is no change in the density of vascular a receptors [22]. Consequently, in HF, coronary vasoconstriction is mediated by the excess norepinephrine and increased release of the coreleased peptide neuropeptide Y [23]. In addition to the direct effects of norepinephrine, the oxidative metabolites of norepinephrine also exert deleterious effects on the heart [24]. High levels of cardiac norepinephrine spillover remain the strongest prognostic marker in HF patients [18].

3. Role of angiotensin II

3.1 Circulating levels of angiotensin II in heart failure HF is associated with increased circulating hormones such as angiotensin II and endothelin. Previous studies have suggested an important role for both angiotensin II and endothelin in modulating sympathetic drive [25]. Several clinical trials have shown that blockade of the RAS, using angiotensin AT1 receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors, reduces mortality and morbidity in patients with HF [5,26]. These drugs decrease the deleterious effects of increased circulating angiotensin II, which are thought to result from its actions to cause vasoconstriction, renal sodium retention, cardiac fibrosis, and increased SNA [27,28]. However, the exact mechanisms of the beneficial effects of ARBs in HF patients remain unclear. Chronic treatment with ACE inhibitors and ARBs has been shown to reduce measures of SNA in HF patients [29,30], but it is uncertain whether this is a direct effect of RAS inhibition or secondary to the hemodynamic improvement that occurs with these drugs. In addition, there is evidence that ARBs can cross the bloodebrain barrier and inhibit the effect of angiotensin II in the brain [31]. We have previously investigated whether circulating angiotensin II was responsible for the increased cardiac SNA during HF. Inhibition of peripheral AT1 receptors using an i.v. infusion of irbesartan did not decrease the elevated cardiac SNA in the HF animals. It is important to note that despite a significant reduction in mean arterial pressure, there was no baroreflexmediated increase in CSNA [32]. These data suggest that circulating angiotensin II may have a minor contribution to the increased cardiac SNA in HF.

3

4

CHAPTER 1 Regulation of sympathetic nerve activity

3.2 Role of central angiotensinergic mechanisms There is extensive evidence that an alteration in central angiotensinergic mechanisms plays an important role in mediating both the increased SNA and the altered reflex regulation of SNA in HF [33,34]. Infusion of angiotensin II into the intracerebroventricular space increases SNA to both the spleen [35] and the kidney [36,37] in rats. This effect of angiotensin II is mediated by the angiotensin II type 1 receptor (AT1R), as infusion of the AT1R antagonist losartan into the intracerebroventricular space blocks the effect of angiotensin II on renal SNA [37]. A previous study has shown that intracerebroventricular (ICV) infusion of angiotensin II increases cardiac SNA in normal conscious sheep [38], suggesting that increased activity of this system could account for the cardiac sympathoexcitation in HF as well. It is also known that AT1R blockers can cross the bloodebrain barrier to varying degrees [31,39]. Therefore, any reduction in SNA may be due to putative inhibition of central angiotensin AT1 receptors. Regarding what might lead to activation of AT1Rs in HF, increased cerebrospinal fluid levels of angiotensin II have been measured in dogs with pacing-induced HF [40]. In addition, increased levels of AT1Rs have been observed in brain nuclei associated with central cardiovascular control in multiple models of HF [41,42]. This evidence for central angiotensin II signaling in HF includes but is not limited to increased mRNA expression of the AT1R in the rostral ventral lateral medulla (RVLM) of rabbits with pacing-induced HF [40,41], and increased AT1R density measured by autoradiography in the subfornical organ, organum vasculosum laminae terminalis, paraventricular nucleus of the hypothalamus (PVN), and the median preoptic nucleus in rats with HF produced by an aortocaval shunt [42]. We have shown that pacing-induced HF in sheep resulted in differential changes in AT1R density; there was a decrease in the area postrema and the NTS at the level of the area postrema but an increase in the paraventricular nucleus of the hypothalamus (Fig. 1.1). The reasons for the discrepancies regarding changes in the AT1R levels in the NTS in the sheep and rodent models of HF are not clear. Irrespective of small differences in species, the data indicate an increase in AT1R within specific brain regions during HF. The following section will focus on the effects of inhibition of these receptors on SNA.

3.3 Blockade of central angiotensin type 1 receptor decreases SNA Administration of the AT1R antagonist losartan into the intracerebroventricular space decreases renal SNA to a greater extent in rats with HF compared with control rats. This is observed both in HF induced by myocardial infarction [43,44] and in rabbits with rapid ventricular pacing-induced HF [41]. In sheep with HF, infusion of losartan significantly reduced cardiac SNA back to almost normal levels (Fig. 1.2) [45]. There was no change in the resting levels of renal SNA in this study, which may reflect the moderate level of HF in these sheep. These results indicate a critical role for central angiotensinergic mechanisms in setting the high levels of

3. Role of angiotensin II

FIGURE 1.1 Original X-ray images of Ang II binding in the hypothalamus and brainstem of one normal (Panel A, C) and one HF animal (Panel B, D). The binding was totally displaced after coincubation with the AT1R antagonist losartan. The histogram shows the density of AT1R binding in major central cardiovascular control nuclei in normal (open bars, n ¼ 5) and HF animals (filled bars, n ¼ 5). Receptor binding densities, determined by in vitro autoradiography, are normalized to control values. HF, heart failure; PVN, paraventricular nucleus of the hypothalamus; SON, Supraoptic nucleus; AP, area postrema; NTS, nucleus of the solitary tract. Results are expressed as means  SE. *P < 0.05 compared with normals using Student’s t-test. Reproduced from Ramchandra R, Hood SG, Watson AM, Allen AM, May CN. Central angiotensin type 1 receptor blockade decreases cardiac but not renal sympathetic nerve activity in heart failure. Hypertension. 2012;59(3): 634e641.

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FIGURE 1.2 Changes in MAP, HR, CSNA, and RSNA over 5 h ICV infusion of losartan in conscious normal (solid line) and heart failure (dashed line) sheep. Time 0 shows resting levels before the start of the losartan infusion. Results are mean  SEM. y indicates significant decrease in HF animals after 5 h Losartan. # indicates significant difference between normal and HF animals at the control time point. Reproduced from Ramchandra R, Hood SG, Watson AM, Allen AM, May CN. Central angiotensin type 1 receptor blockade decreases cardiac but not renal sympathetic nerve activity in heart failure. Hypertension. 2012;59(3): 634e641.

cardiac and renal SNA in HF. Endogenous angiotensin II also contributes to the suppressed baroreflex in HF, as AT1R blockade normalizes the depressed baroreflex control of renal SNA in a rat model of chronic HF [43,46]. The finding that central AT1R blockade in HF restored baseline levels of cardiac SNA and renal SNA in multiple animal models points toward the important role of central angiotensin II in the modulation of SNA. The next sections will focus on the specific sites within the brain that may be responsible for the sympathoexcitation observed in HF.

3.4 Central regions that respond to angiotensin II The finding that central infusion of AT1R blockers can reduce SNA has led to numerous investigations examining the site putatively responsible for the elevated sympathetic drive in HF. We will focus on the data examining the actions of two sympathetic premotor sites: the PVN and the rostral ventral lateral medulla (RVLM) as well as a circumventricular organ, the area postrema.

3. Role of angiotensin II

3.4.1 The role of the paraventricular nucleus of the hypothalamus in heart failure Earlier studies using transsynaptic neuronal transport of pseudorabies virus from the kidney and stellate ganglion showed neurons in the PVN anatomically innervate both the kidney and the heart [47,48]. In particular, there is good evidence that the PVN mediates the SNA response to changes in volume status [49e51]. Volume expansion and right atrial stretch increase the expression of the early gene marker c-fos in parvocellular neurons of the PVN [52], and inhibition of PVN neurons with muscimol attenuated the volume expansion-induced inhibition of renal SNA [53]. Microinjection of angiotensin II into the PVN in normal rats increases both mean arterial pressure and renal SNA [54,55]; this excitation is inhibited by the AT1R antagonist losartan. Endogenous angiotensin II may not regulate baseline levels of renal SNA under normal conditions, as microinjection of losartan into the PVN reduced mean arterial pressure but did not change renal SNA in anesthetized rats in one study [56], although this finding is not universal [57]. Given that HF is associated with volume expansion and significant increases in sympathetic drive to the heart and the kidney, there has been a major interest in determining whether the PVN mediates the increased SNA in HF. Activation of the PVN in HF is indicated by the increased expression of c-fos- as well as Fosrelated antigens in neurons in the PVN [58,59]. In addition, studies in a rat model of HF indicate that the PVN contributes to the increased renal SNA [54,57,60] and that PVN neurons have a higher firing rate. A major factor leading to the increased sympathetic outflow to the kidneys from the PVN in HF appears to be a reduced inhibitory GABAergic input [54,61]. In particular, AT1R mRNA and protein levels are higher in the PVN of rats with HF than controls [57]. This is in line with functional data for renal SNA where microinjection of the AT1R antagonist losartan into the PVN decreases renal SNA in HF rats [57], while the renal SNA response to losartan is greater in rats with HF. We have shown that AT1R within the PVN is upregulated in our sheep model of HF, as assessed by an autoradiography receptor binding assay [62]. In contrast to renal SNA, however, the PVN does not appear to play an important role in modulating cardiac SNA during HF. Both, inhibition of neurons in the PVN and ablation of the PVN do not alter cardiac SNA in the ovine HF model [62]. Taken together, these studies indicate a crucial role for the PVN in modulating SNA to the kidney but not to the heart during HF.

3.4.2 Actions of angiotensin II within the rostral ventral lateral medulla There is good evidence that overactivity of neurons within the RVLM may also play an essential role in the high renal SNA in HF. Microinjection of angiotensin II into the RVLM increases renal SNA in an infarction model of HF in rats [63]. The expression of the AT1R within the RVLM is increased in HF in this model [63,64]. The increase in renal SNA during the development of HF in the pacinginduced model also reflects the upregulation of the AT1R within the RVLM [65].

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These studies suggest that an upregulation of angiotensin II within the RVLM may drive the increase in renal SNA during HF.

3.4.3 Actions of Ang II within the area postrema In addition to sympathetic premotor areas, there is also evidence that the sensory circumventricular organs, areas of the brain without a bloodebrain barrier, play an important role in determining the increased SNA in HF [66e68]. These organs include the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO), and area postrema, which have receptors for numerous circulating hormones, including angiotensin II [69,70], many of which are increased in HF. Therefore, these circumventricular organs may detect humoral signals from the periphery and relay this information to autonomic centers in the brain, which may contribute to the increased SNA in HF [71,72]. A number of studies have implicated the OVLT and SFO in mediating the increase in renal SNA in rodent models of HF [71,72]. In rats with HF induced by myocardial infarction, lesion of the anteroventral third ventricle (AV3V) wall, which includes the OVLT, prevented the increase in renal SNA and improved baroreflex function [67], indicating an important role for this circumventricular organ in mediating the increase in renal SNA. Lesion of the AV3V did increase mortality in rats with HF, but it is unclear if this was due to lesion of the OVLT or other forebrain areas damaged by this lesion. In rabbits with pacing-induced HF, lesion of the area postrema did not reduce resting levels or improve the baroreflex control of renal SNA. However, the ability of an AT1R antagonist to increase the sensitivity of the arterial baroreflex control of renal SNA was prevented, suggesting that, in HF, an action of angiotensin on the area postrema contributes to the reduction in baroreflex sensitivity [68]. In contrast to the results with renal SNA, lesion of the area postrema caused a large decrease in the high levels of cardiac SNA in ovine HF [66]. The finding that there is a decrease in AT1R in the area postrema in this model makes the role of angiotensin II at the area postrema unclear. The pathways from the area postrema to the cardiac sympathetic nerves remain to be elucidated. It is possible that direct efferent projections from the area postrema to the RVLM, which have been described in rabbits [73], play a role in maintaining the increased cardiac SNA in HF. The different responses of cardiac SNA and renal SNA to lesion of the area postrema, both in pacing models of HF, may result from a species effect and/or highlight the differential central control of sympathetic outflow to the heart and kidneys.

4. Actions of angiotensin II within the spinal cord 4.1 AT1R within the spinal cord

In addition to central brain regions, recent studies have examined the importance of angiotensin II within the spinal cord in modulating SNA. In this context, sympathetic preganglionic neurons of the intermediolateral cell column of the spinal cord (IML)

4. Actions of angiotensin II within the spinal cord

are an important site, relaying sympathetic outflow to the heart and the kidney from the RVLM and the PVN [74,75]. Previous studies have shown that sympathetic preganglionic neurons express AT1R in the IML in multiple species, including humans [76], rats [77,78], and sheep [79]. Consistent with previous studies, we found expression of the AT1R in discrete regions of the spinal cord, including the IML, dorsal horn, and around the central canal at spinal segmental levels T1-2 and T11-12 (Fig. 1.3). Interestingly, normal sheep show higher AT1R binding density in the T11-12 sections than the corresponding T1-2 sections. There were no significant differences in AT1R expression of the dorsal horn or around the central canal. The higher levels of AT1R at the level of T11-12 compared with T1-2 mirror the higher baseline levels of sympathetic drive to the kidney compared with the heart.

4.2 Regulation of sympathetic nerve activity by AT1R within the spinal cord As expected, based on the distribution of AT1R in the IML, when angiotensin II is given intrathecally, there is an increase in SNA. In anesthetized rats, intrathecal administration of angiotensin II at the level of T9-10 [80,81] increased splanchnic and renal SNA as well as mean arterial pressure. Additional evidence from conscious normal sheep has shown that intrathecal administration of angiotensin II at T1-2 significantly increased cardiac SNA [82]. Simultaneously recorded cardiac SNA and renal SNA showed that renal SNA did not change when either angiotensin II or losartan was injected at the level of T1-2. These findings indicate that angiotensin II has selective effects on individual neurons at specific locations in the spinal cord; stimulation of sympathetic outflow to the heart at T1-2 and to the kidney at T11-12. It is possible that due to size, the regional selectivity of the intrathecal responses is more pronounced in sheep, although very few studies have recorded from sympathetic nerves to two organs at the same time. In normal conditions, endogenous angiotensin via the AT1R does not play a role in IML sympathetic outflow since infusion of losartan intrathecally does not alter baseline levels of blood pressure [83] but can abolish the dose-dependent increases in mean arterial pressure and SNA in both anesthetized [84] and conscious preparations. Expression of the AT2R within the spinal cord has been shown to have opposing actions to the AT1R, and inhibit SNA [84]. Selective activation of AT2R in the IML evokes hypotension and inhibition of renal SNA, which were abolished completely by AT2R inhibitors in anesthetized rats. Interestingly, blockade of endogenous AT2R in the IML significantly increased baseline mean arterial pressure and renal SNA. These data indicate that AT2R may have an endogenous role in modulation of SNA in the spinal cord, but more studies are needed in this area. Regarding the mechanisms whereby intrathecal angiotensin II alters SNA, a previous study has examined the actions of angiotensin II on sympathetic preganglionic neurons using the whole-cell patch-clamp technique in spinal cord slice preparations. Minoura et al. demonstrated that both silent and firing sympathetic preganglionic neurons in the IML were significantly depolarized by angiotensin II [85]. In addition,

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FIGURE 1.3 Original X-ray images of angiotensin II binding in the spinal cord of a normal (A and C) and a heart failure (HF) sheep (B and D). Panels A and B represent spinal cord sections at thoracic level T1-2, and panels C and D represent spinal cord sections at thoracic level T11-12. The binding was totally displaced after coincubation with the angiotensin type 1 receptor (AT1R) antagonist losartan. Scale bar ¼ 5 mm. The histogram shows the density of AT1R binding in the spinal cord in the normal (open bars n ¼ 5) and heart failure groups (filled bars; n ¼ 5). * denotes a significant difference between the groups using an ANOVA; # denotes a significant difference between the levels at T1-2 and T11-12. P < 0.05. IML, intermediolateral cell column; DH, dorsal horn; CC, central canal. Reproduced from Leversha S., Allen A.M., May C.N., Ramchandra R. Intrathecal administration of losartan reduces directly recorded cardiac sympathetic nerve activity in ovine heart failure. Hypertension 2019;74(4): 896e902.

4. Actions of angiotensin II within the spinal cord

after application of tetrodotoxin, angiotensin II continued to depolarize firing sympathetic preganglionic neurons suggesting both presynaptic and postsynaptic actions of angiotensin II. Application of AT1R antagonist candesartan abolished this depolarization effect indicating a role for the AT1R. It is important to note that when intrathecal injections are used, angiotensin II can also bind to the AT1R in the dorsal horn; these are likely presynaptically located on dorsal root ganglion sensory neurons [86]. While these dorsal root ganglion cells do express AT1R, the sensory modality of these neurons is not known. It is possible that angiotensin II may activate these terminals to induce a spinal reflex activation of sympathetic efferent activity.

4.3 Changes in spinal cord AT1R during heart failure Angiotensin II given within the spinal cord can increase SNA. In sheep with HF, there was increased binding of the AT1R at the level of T1-2 in the IML and a tendency to increased binding in the dorsal horn, but no differences around the central canal (Fig. 1.3). Interestingly, there were no differences in the binding of 125I-[Sar1, Ile8] angiotensin II in the IML, dorsal horn, or central canal between normal and HF sheep at the level of T11-12 (Fig. 1.3). Consistent with the higher binding of AT1R in the spinal cord at the level of T1-2, intrathecal infusion of losartan in the sheep with pacing-induced HF did not change mean arterial pressure but caused a significant reduction in cardiac SNA and heart rate (Fig. 1.4). This inhibition appears to be site-specific since when renal SNA was simultaneously recorded in these animals, there was no change in renal SNA when losartan was injected at the level of T1-2. Our data are consistent with the idea that angiotensin II within the spinal cord may mediate changes in SNA. Importantly, this suggests that endogenous angiotensin II within the spinal cord contributes to the increased cardiac SNA in HF. This finding in a model of HF is similar to what has been observed in renovascular hypertensive rats where the RVLM-mediated increase in renal SNA is inhibited by intrathecal administration of an AT1R blocker [87e89]. When the AT1R blocker losartan was infused into the lateral or fourth cerebral ventricles, there was a long time delay of around 3 h before cardiac SNA levels were reduced to levels observed in normal animals [45,66] (Fig. 1.2). This result contrasts with a shorter delay of 1 h before inhibition of cardiac SNA when losartan is infused via the intrathecal infusion route (Fig. 1.4). This indicates that part of the inhibition of cardiac SNA with losartan infusion in the cerebral ventricles may be mediated by its actions on the spinal cord. Interestingly, infusion of losartan into the cisterna magna for 5 h does not reduce cardiac SNA in HF sheep. However, this infusion would bathe the outside of the spinal cord and would not access the central canal. Therefore, intracisternal infusion of losartan would be unlikely to achieve a sufficient concentration at the IML to alter sympathetic preganglionic neuron activity. Such access issues may contribute to the reason high doses of losartan are required to attenuate sympathetic outflow in patients with HF [90].

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FIGURE 1.4 Changes in mean arterial pressure, heart rate, CSNA, and RSNA in the normal (n ¼ 6) and heart failure (n ¼ 5) groups in response to intrathecal administration of losartan (1 mg/ml/h) at T1-2 in normal (solid lines) and HF animals (dotted lines). N ¼ 4 for the RSNA data. # denotes a significant interaction effect of time X group. If a significant effect of time was found, post hoc analysis was done on each time point versus the baseline level. * denotes a significant post hoc effect of each time point against baseline; P < 0.05 using a two-way ANOVA. Reproduced from Leversha S., Allen A.M., May C.N., Ramchandra R. Intrathecal administration of losartan reduces directly recorded cardiac sympathetic nerve activity in ovine heart failure. Hypertension 2019;74(4): 896e902.

Acknowledgments

5. Conclusions In HF, the increase in the levels of SNA to the heart and the kidney are particularly damaging and are associated with increased mortality. There is a differential effect in the extent of the increase in cardiac versus renal SNA and the time course of the increase in SNA. The finding that infusion of losartan into the brain results in a significant reduction in both cardiac and renal SNA toward normal levels indicates a critical role for central angiotensinergic mechanisms. Previous studies have indicated a critical role for the PVN in setting the increased renal SNA in HF, but surprisingly this does not appear to be the case for cardiac SNA. In contrast, the area postrema plays an important role in modulating cardiac SNA in HF, although the role of angiotensin II in this circumventricular organ is not as clear. Finally, emerging evidence points toward an important role for spinal angiotensin II in modulating SNA to the heart in HF. These findings highlight the important role of central angiotensin II in differential control of SNA, and this extends to both baseline conditions and HF.

6. Future directions It is now clear that angiotensin II within the brain and the spinal cord plays an essential role in mediating the increase in SNA during HF (Fig. 1.5). While the role of the area postrema in mediating the high levels of cardiac SNA in HF is established, the projections from the area postrema to the sympathetic premotor region, which drives this increase in cardiac SNA, are not known and require further investigation. The important role of the PVN in the control of renal SNA but not cardiac SNA in HF further highlights the need to record SNA to different vascular beds and study differential control of SNA in HF. Currently, investigations that have explored the role of the AT1R within the spinal cord in modulating sympathetic drive during HF are limited, and further research into the role of the spinal cord is needed. Increased research into the site-specific actions of central and spinal angiotensin II in HF may open new avenues for therapeutics while further advancing our understanding of this chronic disease.

Acknowledgments Work in the author’s laboratory was supported by grants from the National Health and Medical Research Council of Australia, the Heart Foundation of Australia, the Health Research Council of New Zealand, and the National Heart Foundation of New Zealand.

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FIGURE 1.5 Schematic showing the contribution of angiotensin II type 1 receptors in the central and spinal regions that contribute to the elevated sympathetic nerve activity in heart failure. The plus symbol denotes a contributory action of angiotensin II to the elevated sympathetic nerve activity. CVO, circumventricular organ; PVN, paraventricular nucleus of the hypothalamus, RVLM, rostral ventral lateral medulla; AP, area postrema.

References

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[49] Coote JH. A role for the paraventricular nucleus of the hypothalamus in the autonomic control of heart and kidney. Exp Physiol 2005;90(2):169e73. [50] Deering J, Coote JH. Paraventricular neurones elicit a volume expansion-like change of activity in sympathetic nerves to the heart and kidney in the rabbit. Exp Physiol 2000; 85(2):177e86. [51] Pyner S, Deering J, Coote JH. Right atrial stretch induces renal nerve inhibition and cfos expression in parvocellular neurones of the paraventricular nucleus in rats. Exp Physiol 2002;87(1):25e32. [52] Akama H, McGrath BP, Badoer E. Volume expansion fails to normally activate neural pathways in the brain of conscious rabbits with heart failure. J Auton Nerv Syst 1998; 73(1):54e62. [53] Ng CW, De Matteo R, Badoer E. Effect of muscimol and L-NAME in the PVN on the RSNA response to volume expansion in conscious rabbits. Am J Physiol Ren Physiol 2004;287(4):F739e46. [54] Li YF, Patel KP. Paraventricular nucleus of the hypothalamus and elevated sympathetic activity in heart failure: the altered inhibitory mechanisms. Acta Physiol Scand 2003; 177(1):17e26. [55] Li YF, Wang W, Mayhan WG, Patel KP. Angiotensin-mediated increase in renal sympathetic nerve discharge within the PVN: role of nitric oxide. Am J Physiol Regul Integr Comp Physiol 2006;290(4):R1035e43. [56] Silva AQ, Santos RA, Fontes MA. Blockade of endogenous angiotensin-(1-7) in the hypothalamic paraventricular nucleus reduces renal sympathetic tone. Hypertension 2005; 46(2):341e8. [57] Zheng H, Li YF, Wang W, Patel KP. Enhanced angiotensin-mediated excitation of renal sympathetic nerve activity within the paraventricular nucleus of anesthetized rats with heart failure. Am J Physiol Regul Integr Comp Physiol 2009;297(5):R1364e74. [58] Patel KP, Zhang K, Kenney MJ, Weiss M, Mayhan WG. Neuronal expression of Fos protein in the hypothalamus of rats with heart failure. Brain Res 2000;865(1):27e34. [59] Vahid-Ansari F, Leenen FH. Pattern of neuronal activation in rats with CHF after myocardial infarction. Am J Physiol 1998;275(6):H2140e6. [60] Patel KP. Role of paraventricular nucleus in mediating sympathetic outflow in heart failure. Heart Fail Rev 2000;5(1):73e86. [61] Zhang ZH, Francis J, Weiss RM, Felder RB. The renin-angiotensin-aldosterone system excites hypothalamic paraventricular nucleus neurons in heart failure. Am J Physiol Heart Circ Physiol 2002;283(1):H423e33. [62] Ramchandra R, Hood SG, Frithiof R, McKinley MJ, May CN. The role of the paraventricular nucleus of the hypothalamus in the regulation of cardiac and renal sympathetic nerve activity in conscious normal and heart failure sheep. J Physiol 2013;591(Pt 1): 93e107. [63] Gao L, Wang WZ, Wang W, Zucker IH. Imbalance of angiotensin type 1 receptor and angiotensin II type 2 receptor in the rostral ventrolateral medulla: potential mechanism for sympathetic overactivity in heart failure. Hypertension 2008;52(4):708e14. [64] Gao L, Wang W, Li YL, Schultz HD, Liu D, Cornish KG, et al. Superoxide mediates sympathoexcitation in heart failure: roles of angiotensin II and NAD(P)H oxidase. Circ Res 2004;95(9):937e44. [65] Fahim M, Gao L, Mousa TM, Liu D, Cornish KG, Zucker IH. Abnormal baroreflex function is dissociated from central angiotensin II receptor expression in chronic heart failure. Shock 2012;37(3):319e24.

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[66] Abukar Y, Ramchandra R, Hood SG, McKinley MJ, Booth LC, Yao ST, et al. Increased cardiac sympathetic nerve activity in ovine heart failure is reduced by lesion of the area postrema, but not lamina terminalis. Basic Res Cardiol 2018;113(5):35. [67] Francis J, Wei SG, Weiss RM, Beltz T, Johnson AK, Felder RB. Forebrain-mediated adaptations to myocardial infarction in the rat. Am J Physiol Heart Circ Physiol 2002;282(5):H1898e906. [68] Liu JL, Murakami H, Sanderford M, Bishop VS, Zucker IH. ANG II and baroreflex function in rabbits with CHF and lesions of the area postrema. Am J Physiol 1999; 277(1):H342e50. [69] McKinley MJ, Albiston AL, Allen AM, Mathai ML, May CN, McAllen RM, et al. The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol 2003;35(6):901e18. [70] McKinley MJ, McAllen RM, Davern P, Giles ME, Penschow J, Sunn N, et al. The sensory circumventricular organs of the mammalian brain. Adv Anat Embryol Cell Biol 2003;172:IIIeXII. 1-122, back cover. [71] Wei SG, Yu Y, Felder RB. Blood-borne interleukin-1beta acts on the subfornical organ to upregulate the sympathoexcitatory milieu of the hypothalamic paraventricular nucleus. Am J Physiol Regul Integr Comp Physiol 2018;314(3):R447e58. [72] Yu Y, Wei SG, Weiss RM, Felder RB. TNF-alpha receptor 1 knockdown in the subfornical organ ameliorates sympathetic excitation and cardiac hemodynamics in heart failure rats. Am J Physiol Heart Circ Physiol 2017;313(4):H744e56. [73] Blessing WW, Hedger SC, Joh TH, Willoughby JO. Neurons in the area postrema are the only catecholamine-synthesizing cells in the medulla or pons with projections to the rostral ventrolateral medulla (C1-area) in the rabbit. Brain Res 1987;419(1e2): 336e40. [74] Sevigny CP, Bassi J, Teschemacher AG, Kim KS, Williams DA, Anderson CR, et al. C1 neurons in the rat rostral ventrolateral medulla differentially express vesicular monoamine transporter 2 in soma and axonal compartments. Eur J Neurosci 2008;28(8): 1536e44. [75] Sevigny CP, Bassi J, Williams DA, Anderson CR, Thomas WG, Allen AM. Efferent projections of C3 adrenergic neurons in the rat central nervous system. J Comp Neurol 2012;520(11):2352e68. [76] MacGregor DP, Murone C, Song K, Allen AM, Paxinos G, Mendelsohn FA. Angiotensin II receptor subtypes in the human central nervous system. Brain Res 1995; 675(1e2):231e40. [77] Ahmad Z, Milligan CJ, Paton JF, Deuchars J. Angiotensin type 1 receptor immunoreactivity in the thoracic spinal cord. Brain Res 2003;985(1):21e31. [78] Allen AM, McKinley MJ, Oldfield BJ, Dampney RA, Mendelsohn FA. Angiotensin II receptor binding and the baroreflex pathway. Clin Exp Hypertens Theor Pract 1988; 10(Suppl. 1):63e78. [79] Oldfield BJ, Allen AM, Hards DK, McKinley MJ, Schlawe I, Mendelsohn FA. Distribution of angiotensin II receptor binding in the spinal cord of the sheep. Brain Res 1994;650(1):40e8. [80] Suter C, Coote JH. Intrathecally administered angiotensin II increases sympathetic activity in the rat. J Auton Nerv Syst 1987;19(1):31e7. [81] Yashpal K, Gauthier S, Henry JL. Angiotensin II stimulates sympathetic output by a direct spinal action. Neuropeptides 1989;14(1):21e9.

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[82] Leversha S, Allen AM, May CN, Ramchandra R. Intrathecal administration of losartan reduces directly recorded cardiac sympathetic nerve activity in ovine heart failure. Hypertension 2019;74(4):896e902. [83] Lewis DI, Coote JH. Angiotensin II in the spinal cord of the rat and its sympathoexcitatory effects. Brain Res 1993;614(1e2):1e9. [84] Chao J, Gao J, Parbhu KJ, Gao L. Angiotensin type 2 receptors in the intermediolateral cell column of the spinal cord: negative regulation of sympathetic nerve activity and blood pressure. Int J Cardiol 2013;168(4):4046e55. [85] Minoura Y, Onimaru H, Iigaya K, Homma I, Kobayashi Y. Electrophysiological responses of sympathetic preganglionic neurons to ANG II and aldosterone. Am J Physiol Regul Integr Comp Physiol 2009;297(3):R699e706. [86] Pavel J, Tang H, Brimijoin S, Moughamian A, Nishioku T, Benicky J, et al. Expression and transport of Angiotensin II AT1 receptors in spinal cord, dorsal root ganglia and sciatic nerve of the rat. Brain Res 2008;1246:111e22. [87] Milanez MIO, Nishi EE, Bergamaschi CT, Campos RR. Role of spinal neurons in the maintenance of elevated sympathetic activity: a novel therapeutic target? Am J Physiol Regul Integr Comp Physiol 2020;319(3):R282e7. [88] Milanez MIO, Nishi EE, Mendes R, Rocha AA, Bergamaschi CT, Campos RR. Renal sympathetic activation triggered by the rostral ventrolateral medulla is dependent of spinal cord AT1 receptors in Goldblatt hypertensive rats. Peptides 2021;146:170660. [89] Milanez MIO, Nishi EE, Rocha AA, Bergamaschi CT, Campos RR. Interaction between angiotensin II and GABA in the spinal cord regulates sympathetic vasomotor activity in Goldblatt hypertension. Neurosci Lett 2020;728:134976. [90] Ruzicka M, Floras JS, McReynolds AJ, Coletta E, Haddad H, Davies R, et al. Do high doses of AT(1)-receptor blockers attenuate central sympathetic outflow in humans with chronic heart failure? Clin Sci 2013;124(9):589e95.

CHAPTER

The contribution of angiotensin peptides to cardiovascular neuroregulation in health and disease

2

Ewa Szczepanska-Sadowska, Tymoteusz Zera, Michal Kowara, Agnieszka Cudnoch-Jedrzejewska Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland

1. Introduction Biologically active angiotensin peptides form a family of highly active compounds, playing significant role in the regulation of a variety of vital processes. Together with renin, they form local renineangiotensin systems (RASs) acting in several organs and tissues. At the same time, they cooperate together as the systemic RAS. The harmonized cooperation of the local RASs largely depends on the coordinating function of the central nervous system RAS. Angiotensin peptides are produced locally by cells of several organs, including the brain, heart, kidney, liver, and gastrointestinal system. Regulatory potentialities of particular peptides of this group significantly differ among various cells and organs. The potency and specificity of their action in the target cells largely depends on presence of specific receptors and efficacy of intracellular pathways mediating their action. A growing number of studies provide evidence that the complexity of processes involved in activation of various components of RAS and determining their regulatory potency significantly increases under pathological conditions, especially those affecting the cardiovascular system.

2. The overview of renineangiotensin system organization: cooperation of central and systemic renineangiotensin system Details of organization of the RAS have been described in several previous studies [1e5], and they are briefly summarized in the following. The angiotensin peptides are generated from the angiotensinogen as a result of a proteolytic cleavage by renin. Angiotensin. https://doi.org/10.1016/B978-0-323-99618-1.00009-X Copyright © 2023 Elsevier Inc. All rights reserved.

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In the kidney, renin is synthesized as prorenin in the juxtaglomerular cells of terminal afferent arteriole and initiates generation of angiotensins from locally synthesized or circulating angiotensinogen. Synthesis of renin increases upon activation of the renal sympathetic nerves, and subsequent release of catecholamines and stimulation of b1 receptors. The release of renin in the kidney is also under control of several local factors such as hypoxia, reduced sodium content in the macula densa cells, and numerous hormonal and humoral factors (see Section 5). The overview of the cleavage cascade engaged in formation of specific components of the RAS is presented in Fig. 2.1. Briefly, preprorenin and prorenin are enzymatically converted to renin, which is a highly potent enzyme. Renin acts on the N-terminus of its own substratedangiotensinogen (Agt) cleaving a decapeptide angiotensin I [(Ang I, Ang-(1e10)], which is converted either to highly active angiotensin II [(Ang II, Ang-(1e8)] by angiotensin-converting enzyme 1 (ACE1) or to Ang-(1e9) by angiotensin-converting enzyme 2 (ACE2). Ang(1e7), which is another biologically potent peptide of the RAS system, can be cleaved either from Ang-(1e9) by ACE1 or from Ang-(1e8) by ACE2. Other components of the RAS system [Ang III, Ang-(2e8); Ang IV, Ang-(3e8); Ang-(1e5), Ang-(5e8); Ang-(1e12)] are produced by enzymatic cleavage performed by other enzymes, such as aminopeptidases, which make a scission at the N-terminus of peptides and carboxypeptidases that act at the carboxy terminus or by endopeptidases.

FIGURE 2.1 The main components of the renineangiotensin system engaged in the regulation of the cardiovascular system and water and electrolyte balance.ACEdangiotensin-converting enzyme inhibitor; ACE1, ACE2d, angiotensin-converting enzymes; APA, APNdaminopeptidases; AT1RdAng II and Ang III receptors; AT2RdANG II receptors; ATR4dAng IV receptors; MasRdAng-(1e7) receptors.

2. Cooperation of central and systemic RAS

The main source of Agt is liver. Angiotensinogen is also locally synthetized in the brain [6,7], and astrocytes appear to be the main source of the protein in the central nervous system [8,9]. However, neurons of discrete regions of mouse brains, specifically the subfornical organ (SFO), the mesencephalic trigeminal nucleus, and the external lateral parabrachial nucleus, also express Agt [10]. Also neurons located in the paraventricular nucleus (PVN), the supraoptic nucleus (SON), and the accessory magnocellular nucleus were found to have positive immunostaining for Agt and Ang II [11]. Expression of Agt in pre/neonatal period seems to be more generalized and was found in astroglial cells of the hypothalamus and the brainstem, the subcortical, and cortical regions and in neurons present in limbic and sensorimotor regions of the brain [12]. Although some controversy exists how effective the local expression of renin is in the brain and whether the key source of renin activity in the brain is derived from the enzyme present in blood in the cerebral circulation [13,14], it is generally accepted that renin and prorenin can be effectively expressed in the central nervous system [15e18]. Experiments in double-transgenic mice expressing enhanced green fluorescent protein (eGFP) driven by the renin promoter and beta-galactosidase (beta-Gal) driven by the human Agt promoter revealed that both Agt and renin are expressed in adjacent cells in the SFO, the rostral ventrolateral medulla (RVLM), and hippocampal CA 1e3 regions [19], indicating that effective formation of Ang II is possible in the brain, including the cardiovascular centers. Accumulating evidence indicates that in addition to classic isoform of renin, a shorter form of the enzyme termed renin-b with expression restricted to the brain has been found in the neurons. It has also been suggested that this intracellular form of renin participates in the synthesis of Ang II that is subsequently released as a neurotransmitter [17,20e22]. The angiotensin-converting enzyme of type 1 (ACE, ACE1), which is the main convertor of angiotensin I (Ang I), acts predominantly in the lungs. ACE2, which is the membrane-bound metalloproteinase, cleaves Ang-(1e8) to Ang-(1e7). It also hydrolyzes other peptides, such as apelin, kinins, (des-Arg9)-bradykinin, neurotensin, and dynorphin A-(1e13) [23]. In many respects, and especially with regard to the regulation of the cardiovascular system, Ang-(1e7) exerts opposite effects to Ang II. Regulatory properties of Ang-(1e7) have been intensely investigated in context of its protective capability in cardiovascular diseases [24e28]. Besides, growing evidence indicates involvement of ACE2dAng-(1e7) axis in the regulation of glycemia through actions exerted in the pancreatic, hepatic, and gastrointestinal cells [29] (see also Section 9). It was shown that Ang-(1e7) plays an essential role in the regulation of intestinal absorption of neutral amino acids, particularly of tryptophan, and it has been suggested that activation of ACE2 in the gastrointestinal tract may regulate substrate availability for neurotransmitters synthesis [30,31] (see also Section 9). Recent studies revealed that ACE2 plays a key role in cellular SARS-CoV2 invasion [32,33] (see also Section 6).

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CHAPTER 2 The contribution of angiotensin peptides

Studies on spatial distribution of ACE2 in the brain revealed that ACE2 is well expressed in the regions engaged in the regulation of cardiovascular and cardiorespiratory functions. Namely, they have been found in the olfactory bulb, the posterior cingulate, and temporal cortex; in the PVN and SON; in the substantia nigra, ventral tegmental area, the dorsal raphe nucleus, and the parabrachial nucleus (PBN); in the reticular nuclei, gigantocellular reticular, and retrotrapezoid nuclei; and in the area postrema (AP), the nucleus of the solitary tract (NTS), the RVLM, the dorsal motor nucleus of the vagus (DMNV), and the nucleus ambiguous [28,30,33]. Using pharmacological and molecular methods, it was possible to show that angiotensin peptides interact with AT1R, AT2R, AT4, and MasR receptors, which belong to G proteinecoupled receptors. In rodents, AT1Rs receptors are subdivided into AT1a and AT1b receptors. Stimulation of AT1R activates multiple intracellular enzymatic pathways, such as phospholipase C (PLC), phospholipase D, phospholipase A2 (PLA2), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and metalloproteinases (MMP). Mobilization of these pathways results in consecutive stimulation of other enzymes and highly active proteins, such as cyclooxygenases, lipooxygenases, cytochrome P450 enzymes, mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinases (JNK), extracellular signaleregulated protein kinases 1 and 2 (ERK1/2), and some transcription factors (NF-kB, AP-1, HIF-1a). There is also evidence for functional cross-talk between the intracellular signaling pathways of AT1R and other angiotensin receptors [4,34e36]. Stimulation of AT2R causes activation phosphotyrosine phosphatases and inactivation of mitogen-activated protein kinases, activation of potassium channels, activation of phospholipase A2, and generation of arachidonic acid derivatives [5,35,37,38]. Effects of Ang II depend on proportion of types of receptors, which are stimulated. Binding to AT1 receptor (AT1R) results in activation of the sympathetic system, vasoconstriction, oxidative stress, inflammation, and fibrosis, whereas activation of AT2 receptor (AT2R) and Ang-(1e7) receptor promotes opposing effects. Prolonged activation of RAS is associated with Ang IIdAT1R deleterious effects [4,35,39e42]. AT1 receptors are present in the brain, heart, and vessels, and in the renal glomeruli, tubules, vessels, and medullary interstitial cells. In the brain, high density of AT1Rs has been found in the circumventricular organs (CVOs), which lack the bloodebrain barrier (BBB), and in several cardiovascular regions. Specifically they are present in the SFO, the organum vasculosum of the lamina terminalis (OVLT), the AP, the median preoptic area (MnPO), the PVN, the nucleus of the tractus solitarius (NTS), and the ventrolateral medulla (VLM) [39,41,43e47]. It has been shown that angiotensin IV (Ang IV) protects from harmful activity of Ang II in the cardiovascular system and exerts procognitive effects [48e52]. Autoradiography and functional studies provide evidence for presence of AT4 receptors in the brain, heart, vessels, and kidney [49,53e56]. At the cellular level, Ang IV stimulates AT4 receptor (AT4R), which has been identified as insulin-regulated

3. Cooperation of the brain RAS with the autonomic nervous system

aminopeptidase (IRAP). In the brain, it interacts also with hepatocyte growth factor/ c-Met receptor pathway [57,58]. Ang-(1e7) activates the Mas receptor (MasR) and subsequently the ACE2d Ang-(1e7)dMasR axis [59e61]. Similarly, as other angiotensin receptors, MasRs are present in the brain, cardiovascular system, and the kidney [59,62,63].

3. Cooperation of the brain renineangiotensin system with the autonomic nervous system: interactions with the sympathetic, parasympathetic, and enteric systems The RAS affects activity of the sympathetic and parasympathetic divisions of the autonomic nervous system at the level of cardiovascular centers of the brainstem and the hypothalamus, and by acting on afferent and efferent pathways involved in the cardiovascular control. These interactions involve both the local brain RAS and Ang II present in the blood stream [14,64,65]. All components of the RAS are expressed in the key cardiovascular centers of the central nervous system [16,46]. The effects of RAS on the sympathetic branch of the autonomic nervous system have been studied since 1960, when early experiments in dogs revealed that the pressor effect of intravenously administered Ang II partially depends on central mechanism involving sympathetic response [66]. Furthermore, experiments in humans showed that intravenously administered Ang II at pressor doses inhibits sympathetic nerve activity by activating arterial baroreflex. However, this inhibition is significantly weaker in comparison with phenylephrine-induced activation of baroreflex, and when blood pressure increase is prevented by nitroprusside infusion to inactivate the arterial baroreflex, the peripherally administered Ang II causes increase in the muscle sympathetic nerve activity (MSNA) [67]. A large body of evidence shows that brain Ang II and AT1Rs are critically involved in winding up sympathetic activity to the heart, vasculature, and kidney with the key neural pathway involving connections between the SFO, PVN, RVLM, and the intermediolateral nucleus (IML), and the AP with the NTS and CVLM [14,16,64]. Angiotensinergic projections from the PVN stimulate AT1Rs in the RVLM and excite pressor neurons of the RVLM [68]. In addition, direct pathways from the PVN to the sympathetic neurons of the IML in the spinal cord are activated by Ang II acting on AT1Rs in the SFO [69]. Furthermore, AT1Rs are located in the presynaptic terminals on the sympathetic neurons of the IML at the thoracic spinal cord [70]. Thus, Ang II may bind to AT1Rs at all organizational levels of key structures involved in the sympathetic outflow. Experiments in rodents show that targeted genetic upregulation of specific components of RAS, such as Agt and/or renin in the central nervous system, leads to sympathoexcitation and increase in arterial blood pressure [71e73]. In this light, mice lacking brain-specific renin-b showed increased expression of AT1Rs in the PVN and increased expression of

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CHAPTER 2 The contribution of angiotensin peptides

classic isoform of renin in the RVLM accompanied by enhanced responsiveness of the renal sympathetic nerves and suggesting that intracellular renin-b inhibits expression of renin [22]. In contrast to classic RAS, upregulation of ACE2dAng(1e7)dMasR axis or silencing (pro)renin receptor exerts sympathoinhibitory and pressure-lowering effects, especially under condition of hypertension or heart failure [74e78]. However, studies investigating the direct effects of Ang-(1e7) on sympathetic activity have provided varied results, with both excitatory and inhibitory effects on the sympathetic activity. Specifically, in rats, blockade of MasR for Ang-(1e7) in the PVN decreases sympathetic activity [79,80], which is suggestive of sympathoexcitatory effect of Ang-(1e7) in the PVN. However, Ang-(1e7) administered into the NTS exerts sympathoinhibitory effect in rats [81]. In anesthetized rabbits, microinjections of Ang-(1e7) into the RVLM increase sympathetic activity, whereas Ang-(1e7) administered into the CVLM attenuates sympathetic activity; however, the responses were observed for high doses of the peptide, suggestive of insignificant role of Ang-(1e7) under physiological conditions [82]. Nonetheless, Ang-(1e7) injected into the RVLM had also pressor effect in awake rats [83]. Furthermore, experiments in brainstem slices indicate that the plausible target of Ang-(1e7) in the RVLM are astrocytes [84]. In addition to the locally generated angiotensins in the brain, neurons of CVOs, including the SFO and the AP, express AT1Rs and respond to Ang II present in the blood and the cerebrospinal fluid [44,85,86]. Binding of Ang II to AT1Rs in the SFO or the AP results in blunting of the baroreflex and sympathoexcitation in normotensive animals and in various models of cardiovascular pathology [87e90]. Furthermore, Ang II microinjected into the AP predominantly causes inhibition of the NTS neurons in brainstem tissue slices [91]. Furthermore, the pressor and subpressor doses of intravenous Ang II were shown to activate the RVLM glutaminergic neurons increase turnover of glutamate and glycine in the RVLM, decrease baroreflex sensitivity, and reset the baroreflex to higher blood pressure [92,93]. In addition, high expression of Agt was found in the AP, the SFO, and the OVLT [6,94]. In addition, local activity of the ACE in the forebrain containing CVOs is involved in tonic excitation of the renal sympathetic nerves [95]. This is further corroborated by findings showing that selective ablation of Agt expression in the SFO effectively abolishes pressor response to activate brain angiotensinergic system [96]. These findings indicate that Ang II may be also locally synthetized in the CVOs and thus exert its sympathoexcitatory effects independently of Ang II present in the bloodstream. The sympathoexcitatory action of the brain RAS also involves resetting of the baroreflex toward higher values of blood pressures, blunting sensitivity of the baroreflex, and enhancing arterial chemoreflex [14,64,87,97]. Microinjections of Ang II into the NTS in in situ braineheart preparations in rat were shown to attenuate the baroreflex-mediated bradycardia and to selectively attenuate sympathoinhibition of the inferior cardiac nerve and midthoracic sympathetic chain, but not the lower thoracicelumbar chain [98]. Blockade of the AT1Rs within the NTS, but not in adjacent regions nor the AP, reversed developmental attenuation of the cardiovagal

3. Cooperation of the brain RAS with the autonomic nervous system

component of the baroreflex in preweaned rats [99]. Furthermore, stimulation of AT1Rs in the NTS selectively blunts the sympathoinhibitory component of the arterial baroreflex but has no effect on the arterial chemoreflex-evoked sympathoexcitation [100]. Contrary to Ang II and AT1Rs, the ACE2dAng-(1e7)dMasR axis increases sensitivity of the baroreflex. For example, intracerebroventricular administration of Ang-(1e7) improves the vagal component of the baroreflex in renine transgenic rats [101]. RAS also affects the afferent sensory pathways involved in the cardiovascular reflexes. Specifically, baroreceptor afferent neurons located in the nodose ganglion express AT1Rs and AT2Rs [102,103]. Ang II acting via AT1Rs appears to decrease the membrane excitability of these aortic baroreceptor neurons in male rats, by NADPH oxidase/superoxide-dependent mechanism [102,104e106]. Such decreased excitability should contribute to depressed arterial baroreflex in cardiovascular and metabolic diseases. However, some studies indicate that Ang II has no effect on excitability of myelinated A-type baroreceptor afferents and that AT1Rs are not significantly involved in Ang II-mediated changes in the nodose ganglion neurons’ electrical properties [103,107]. Furthermore, Ang II may increase excitability of the nodose ganglion neurons associated with the arterial baroreceptors via AT2Rs, especially in females. Specifically, expression of AT2Rs in the nodose ganglia is significantly higher in female than male rats and is strongly associated with Ah-type afferent barosensitive fibers [103], a subtype of myelinated barosensitive afferents that are abundantly and distinctly present in the aortic depressor nerve of female rats [108]. Of note, the expression of AT2Rs in the afferent barosensitive fibers was strongly dependent on estrogens [103]. Thus, it is plausible that at least in the females, Ang II may increase sensitivity of the baroreflex via AT2Rdependent mechanism. Nonetheless, systemic administration of losartan, AT1R antagonists, was shown to reverse depression of the aortic nerve activitydpressure relationship in male rats with hypertension induced by coarctation of the aorta [109], indicating involvement of Ang II and AT1Rs in desensitizing the baroreceptor afferent fibers. Angiotensinogen, ACE and AT1Rs, but not renin, are also expressed locally in the chemoreceptive glomus cells of the carotid bodies [110e115] and exposure to hypoxia robustly upregulated AT1Rs in the carotid body [112,116]. Ang II acting via AT1Rs in the CB enhances intracellular calcium in the glomus cells [114], increases firing of the carotid sinus nerve, and leads to sympathoexcitation [87,97,115,117e119]. In contrast to AT1Rs, blockade of AT2Rs was found to have insignificant effect on the glomus chemosensitive cells [114]. Furthermore, there is evidence that Ang II directly stimulates neurotransmission in the autonomic ganglia to induce release of catecholamines into the bloodstream [120] and release of noradrenaline from the sympathetic nerve endings [121]. Thus, Ang II may further augment the centrally mediated sympathoexcitation by its peripheral action; however, importance of this mechanism for increased sympathetic outflow to cardiovascular system remains unclear.

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CHAPTER 2 The contribution of angiotensin peptides

Growing body of evidence indicates that RAS also affects the parasympathetic branch of the autonomic nervous system not only by resetting the baroreflex but also by acting on the brainstem parasympathetic centers and interacting with the vagus nerve and its ganglia [65]. Specifically, microinjections of low dose Ang II into the DMNV decrease the heart rate in rats [122], and upregulation of AT2R in the NTS/DMNV complex improves the vagal component of the baroreflex [123,124]. Furthermore, systemic blockade of AT1Rs enhances bradycardia induced by the vagal nerve stimulation, whereas intravenous administration of Ang II has the opposing effect [125]. In addition, Ang II attenuates release of acetylcholine from the nerve terminals of the cardiac vagus and attenuates negative chronotropic effect of the vagus stimulation [126,127]. In contrast to the cardiac branch of the vagus, peripherally acting Ang II increases activity of the vagus nerve celiac efferents, which in turn stimulates the splenic nerve and release of proinflammatory factors in the spleen that contribute to the prohypertensive phenotype [128,129]. In conclusion, RAS plays an important role in regulation of sympathetic and parasympathetic divisions of the autonomic nervous system and cardiovascular reflexes. The effects of RAS are present in the key cardiovascular centers of the hypothalamus and the brainstem, in the spinal cord, and the autonomic ganglia and nerve fibers/terminals. The CVOs, especially the SFO and AP, provide interface for interactions of the central nervous system with systemic RAS. The classic RAS promotes sympathoexcitation, exerts pressor effects, and limits vagal activity to the heart, whereas the ACE2dAng-(1e7)dMasR axis mostly exerts sympathoinhibitory and pressure-lowering effects, especially under condition of hypertension or heart failure.

4. Role of the brain renineangiotensin system in the regulation of watereelectrolyte balance RAS plays crucial role in the regulation of intake and excretion of water and electrolytes, being thereby a primary player in maintenance of watereelectrolyte balance.

4.1 Regulation of sodium and water intake Shortly after discovery of renin and angiotensin peptides, it became evident that several elements of the brain RAS regulate thirst and sodium appetite, whereas the kidney RAS regulates excretion of sodium and water and that these processes are partly mediated by other hormones, mainly aldosterone and vasopressin [130e132]. Stimulation of thirst and sodium appetite by renin and angiotensins has been described in many species, although there are significant interspecies differences regarding their effectiveness in the regulation of sodium appetite. Both water and sodium intakes are significantly enhanced by systemic and intracerebroventricular (ICV) application of Ang II or Ang III in rats, mice, dogs, pigs, and baboons

4. Brain RAS in the regulation of water-electrolyte balance

[133e138]. In the sheep and cattle, Ang II exerts the dipsogenic effect, but it does not stimulate sodium appetite [139e141]. Regulation of thirst in the man by Ang II was investigated only in one investigation [142]. The results of this study were not convincing, because the dipsogenic action of intravenous infusion of Ang II occurred only in 4 out of ten healthy subjects, and the total result was not significant. Ang-(1e7), which acts oppositely to Ang II in blood pressure regulation, does not play antagonistic role in the regulation of water intake. It has been shown that Ang-(1e7) does not influence baseline water and sodium intake and release of vasopressin, and acts in synergy with Ang II in the regulation of dehydration-induced thirst [143,144]. Studies based on blockade of specific angiotensin receptors, or application of specific oligonucleotides inhibiting formation of angiotensins, revealed that the stimulatory effects of Ang II and Ang III on water and sodium intakes during water deprivation and hypovolemia are mediated mainly by AT1Rs; however, an engagement of AT2R in stimulation of thirst during water deprivation has been also suggested [137,145e149]. Dipsogenic effectiveness of Ang II significantly differs among the species [147,150,151]. The neural network involved in the regulation of thirst and salt appetite comprises multiple brain regions. Both water and sodium intakes are regulated by neurons of the brain cortex, anterior and lateral portions of the hypothalamus (mainly PVN), the anteroventral third ventricle wall (AV3V), the circumventricular organs (OVLT, SFO, AP), and the brainstem. Neurons of the anterior cingulate cortex, septum amygdala, insula, OVLT, and SFO are involved mainly in stimulation of thirst, whereas neurons of the PBN, NTS, and the AP are engaged in the inhibition of drinking and the preabsorptive satiation [85,152e154]. Angiotensin II regulates water intake in cooperation with vasopressin. The neural network involved in the regulation of thirst and release of vasopressin comprises groups of neurons located in the same brain regions, and Ang II is a potent stimulator of AVP release. Vasopressin, similarly as Ang II, stimulates thirst in the dog and the rat, and its dipsogenic effect can be abolished by blockade of AT1Rs. The latter finding suggests that stimulation of thirst by vasopressin requires concomitant stimulation of AT1Rs [132,152,155e158]. It is likely that mineralocorticoids can cooperate with Ang II in the regulation of sodium appetite. For instance, it has been shown that in the rat with renovascular 2K1 Chypertension Ang II enhances sodium intake in cooperation with aldosterone [159].

4.2 Kidney and gastrointestinal system Excretion and absorption of sodium and water are regulated by angiotensins through actions exerted in the kidney and the gastrointestinal system. Activity of the local RASs in these target regions is regulated by environmental factors, but it is also under control of the autonomic nervous system, which is regulated by the brain RAS and other regulatory systems. Intrarenal and gastrointestinal angiotensin receptors

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can be addressed by locally released angiotensins and by those delivered by circulating blood. In the kidney, compounds of locally acting RAS play a significant role in the regulation of the renal circulation, and tubular secretion and absorption through direct autocrine and paracrine actions. Effect of stimulation of the renal nerves on secretion of renin depends on the intensity of stimulation. At higher levels of stimulation, release of renin may be associated with increased sodium reabsorption [1,160e162]. Autoradiographic and radioligand binding studies provide evidence for presence of AT1, AT2, AT4, and Mas receptors in the vessels, and in the cortical and medullary renal tubules. Intrarenal application of Ang II exerts vasoconstriction of cortical and medullary vessels and modulates sodium and water retention. There is compelling evidence that an excessive production of Ang II and stimulation of AT1Rs in the kidney exert pathogenic effects brought about by reduced blood perfusion, sodium retention, and reactive oxygen species production [1,163e166]. Vasoconstrictory capability of Ang II in the kidney is effectively modulated by action of several locally operating vasoconstrictory and vasodilatory factors, mainly vasopressin and other angiotensins, prostaglandins, growth factors, cytokines, nitric oxide, and ROS [167e172]. In the renal glomeruli cells, Ang I can be metabolized to Ang-(1e7) by aminopeptidase A. In the kidney, ACE2 / Ang-(1e7) pathway plays a protective role and opposes negative effects of Ang II. Specifically, Ang-(1e7) antagonizes vasoconstrictory, excretory, and growth-promoting effects of Ang II and decreases sodium transport in the proximal tubule, loop of Henle, and the collecting duct, reducing thereby sodium and water retention. It is likely that the beneficial effects of Ang(1e7) are potentiated in hypertension [1,173e175]. There is compelling evidence that kidney diseases are associated with inappropriate function of the RAS cascade products and that an excessive formation of Ang II and stimulation of renal AT1R exert pathogenic effects that result from diminished renal blood perfusion and hypoxia, and from elevated sodium retention and reactive oxygen species generation [168,170,176]. Suppression of RAS by inhibition of ACE or blockade of angiotensin receptors in patients suffering from diabetic and nondiabetic nephropathy or from the metabolic syndrome exerts beneficial effects, as indicated by reduction of the doubling of the baseline serum creatinine concentration [177e180]. However, it has not been determined whether the beneficial effects of these compounds result from their direct action in the kidney or from the improvement of the hemodynamics due to suppression of the systemic and central action of Ang II [163,176,181].

5. Role of RAS in stress, depression, and COVID-19

5. Other effects of the brain renineangiotension system affecting the cardiovascular regulation: role of renineangiotension system in stress, depression, and COVID-19 5.1 Stress and depression

The medical term of stress is attributed to several states of emotional strain that may occur in cardiovascular diseases, such as elevated alertness, anxiety, emergency, tissue injury, or pain [182e185]. Several studies provide evidence that there are strong mutual relations between stress and RAS [35,51,186e189]. Stress of different modalities activates RAS both in the brain and in peripheral organs. The brain regions activated during stress, such as the hypothalamopituitary axis, PVN, septum, amygdala, and the brain stem cardiovascular and respiratory areas (NTS, PBN, RVLM, gigantocellular reticular, and retrotrapezoid nuclei), are furnished with angiotensin receptors. In experiments on rats, inhibition of ACE by oral administration of captopril significantly reduced cardiovascular responses to stress in chronically stressed rats both in infarcted and in sham-operated animals [190]. Moreover, it has been shown that chronic mild stress increases expression of AT1Rs in the cardiovascular regions of the brain and the kidney [191] and that treatment with AT1R antagonist (losartan) reduces elevation of the sympathetic tone and decreases reduction of the parasympathetic tone induced by chronic repeated stress [192]. The cardiovascular pathology associated with myocardial infarction or hypertension increases activation of the brain RAS. It has been shown that the myocardial infarction results in elevation of expression of AT1R in the brain, heart, and kidney [193,194]. Moreover, Ang II was found to increase cardiovascular response to stress, and this effect was potentiated after the myocardial infarction [195]. On the other hand, inhibition of ACE or blockade of AT1Rs normalized the exaggerated cardiovascular responses to stress after the myocardial infarction and in experimental models of hypertension [187,193e198]. Chronic stress frequently results in depression, which may worsen comfort of the patient suffering from cardiovascular diseases. Studies on experimental models of depression and clinical trials show that depression is associated with significant changes in the brain, which can be visualized in the regions provided with components of RAS [199e201]. Studies analyzing polymorphisms of genes encoding for components of RAS provided evidence that some types of polymorphism of AT1R may predispose to depression. In this line, significant association of depression and angiotensin receptor type 1 (A1166C) CC genotype has been reported, and significant differences in haplotype-tagging single nucleotide polymorphism (htSNP) of AT1Rs between depressed patients and control subjects have been described (rs10935724 and rs12721371) [202,203]. Analysis of association of ACE gene insertion/deletion (I/D) (rs1799752) revealed that the deletion allele, which is characterized by

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elevated activity of the enzyme, is associated with greater risk of hypertension, myocardial infarction, and heart failure; however, this polymorphism was not associated with depression [204]. Deletion of Agt gene in the rat transgenic model [TGR(AsrAOGEN)0680] with reduced synthesis of Agt in the brain resulted in creation of animals manifesting depressive-like behavior, which could be reversed by intracerebroventricular (ICV) administration of Ang-(1e7). In addition, ICV infusion of Ang-(1e7) reduced ACE activity and expression of AT1Rs in the hypothalamus of the transgenic animals [205,206].

5.2 COVID-19 Growing evidence indicates that the regulation of the cardiovascular system by angiotensins can be significantly affected in the coronavirus disease (COVID-19). On May 13, 2020, WHO annunciated COVID-19 as the pandemic disease, and subsequently, the first guideline and strategy on therapeutics and COVID-19 have been declared [207]. In parallel, intense studies concerning pathophysiology of COVID-19 disease revealed that SARS-CoV-2, which is the primary virus responsible for spreading of the infection at the cellular level, interacts with ACE2. It has been shown that the extracellular domain of ACE2 plays a function of membrane receptor for the S1 subunit of the spike-S protein of SARS-CoV-2, which binds to the ACE2. The binding initiates the proteolytic cleavage of SARS-CoV-2 by proteases and its penetration into the cell that is followed by the intracellular replication [32,208e211]. COVID-19 infection belongs to multiorgan diseases affecting cardiovascular, respiratory, and gastrointestinal systems and evoking multiple cerebrovascular disorders, such as dizziness, headache, ataxia, epilepsy, and loss of consciousness. Experimental studies and clinical observations provide evidence that several symptoms of COVID-19 infections can be explained by disturbances of the RAS activity, although the results are not explicit. It is very likely that COVID-19 infection can be associated both with activation and with downregulation of the ACE2 pathway, depending on the stage of the disease [32,212,213]. The studies performed on swine have shown that prolonged infusion of Ang II or blockade of ACE2 causes several symptoms characteristic for COVID-19 infection, such as increased pulmonary artery pressure, hypoxia, elevated coagulation, alveolar damage, impaired pulmonary perfusion, and acute tubular necrosis. These effects can be significantly reduced by blockade of angiotensin receptors, and accordingly, it has been concluded that the RAS imbalance accounts for a number of clinical futures of COVID-19 infection [214]. SARS-COV and SARS-Cov-2 manifest significant tropism to cells expressing ACE2 in the respiratory, cardiovascular, nervous, and gastrointestinal systems, and ACE2 plays a key role in the processes of cellular invasion and cellular pathology in these systems. It has been also postulated that inappropriate receptive and/or regulatory functions of the ACE2 pathway determine susceptibility to the COVID-19

6. Brain RAS in cardiovascular regulation in hypertension

infection and have impact on severity of complications of other diseases [208,211,215e218]. Disturbances of the central nervous system function belong to frequent symptoms of COVID-19, and there are reasons to believe that they may result from inappropriate action of ACE2 in the brain. ACE2 is present in CSF and choroid plexus and in the cells forming BBB (endothelial cells, pericytes). It has been postulated that ACE2 promotes penetration of the SARS-CoV-2 into the brain through BBB and allows invasion of the virus to the neurons and glial cells. In this line, it has been shown that the SARS-CoV-2 virus associates with ACE2 of endothelial cells and triggers RhoA activation, followed by BBB disruption. This process is facilitated by activation of the transmembrane protease serine 2 (TMPRSS2) and cathepsin L. Besides, it has been shown that SARS-CoV-2 can cause disruption of the basement membrane and cross the BBB via the transcellular pathway without obvious alteration of tight junctions [219e224]. In summary, multiple studies show strong associations between SARS-CoV-2 infection, ACE2 dysfunction, and neurological disturbances in COVID-19 disease. Taking into account essential involvement of ACE2-Ang-(1e7) pathway in the regulation of the cardiovascular functions, it is very likely that the cardiovascular disorders occurring in COVID-19 are caused by inappropriate activation of ACE2 in the brain and the cardiovascular system [33].

6. Role of the brain renineangiotensin system in cardiovascular regulation in hypertension Increased central expression of classic RAS is associated with high blood pressure in numerous animal models of hypertension. Upregulation of components of the RAS in the cardiovascular centers via genetic manipulations or targeted viral transductions leads to sympathoexcitation and hypertension, whereas downregulation of RAS has opposite effects [15,16,225]. The effects of central ACE2dAng-(1e7)d MasR axis and AT2R in hypertension are generally considered depressor; however, actions of Ang-(1e7) appear to be site-specific in regard to distinct cardiovascular centers [225]. Experiments in mice show that genetic upregulation and increased availability of Agt in the brain lead to increased sympathetic tone to the cardiovascular system [71] and development of hypertensive phenotype, especially when combined with enhanced renin activity [72]. This is in line with findings showing that expression of Agt and AT1R mRNA is increased in the NTS and the AP in hypertensive SHR rats in comparison with normotensive controls [226]. Furthermore, in these hypertensive rats, lowering of blood pressure by exercise training is associated with decrease in expression of Agt mRNA in the NTS and the AP [226]. Thus, increased brain expression of Agt, the substrate for renin, is associated with hypertension.

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Upregulation of renin in the renin transgenic rats (mRen2) 27 leads to centrally mediated sympathoexcitation and hypertension [227], and intracerebroventricular administration of renin inhibitor aliskiren prevents sympathetic overactivity and development of high blood pressure in Dahl-salt sensitive rats [228]. However, it should be noted that selective knockout of renin in neuronal and glial cells had no effect on cardiovascular parameters or watereelectrolyte balance in normotensive mice [229], suggesting irrelevant role of renin in the brain under physiological conditions. In contrast, ablation of the neuronal renin-b in the brain leads to upregulation of AT1Rs in the PVN and increased expression of renin in the RVLM with consequent development of neurogenic hypertension in mice [22]. Although expression of renin in the central nervous system is low, the enzyme may bind to its prorenin receptor (PRR) expressed on neurons and glia, and this has been implicated in greatly increased efficiency of Agt conversion to Ang I by renin [230]. Thus, interaction of renin with PRR may greatly enhance formation of Ang II in the central nervous system and contribute to elevation of blood pressure [225,231]. In this light, knockdown of PRR in the brain in mice decreases sympathetic activity and prevents development of DOCA-salt hypertension [232,233] and Ang II-induced hypertension [234]. In SHR rats, targeted ablation of PRR in the SON was shown to attenuate hypertension [235]. Furthermore, stimulation of PRR on the microglia promotes neuroinflammation in the cardiovascular centers and development of hypertension [236]. Increased expression of PRR has been found in the PVN, the RVLM [237], and the SFO [238] obtained postmortem from hypertensive patients. Thus, renin and PRR appear to play an important role not only in experimental models but also in human hypertension. Amassed evidence indicates that expression of AT1Rs is present in the CVOs and brain nuclei involved in the control of arterial blood pressure, and their stimulation leads to pressor and sympathoexcitatory responses that are enhanced in various models of arterial hypertension. AT1Rs present in the CVOs provide interface for coupling the peripheral and central RAS, as the SFO and the AP neurons can be stimulated by Ang II present in the CSF/plasma [69,239]. Activation of angiotensinergic pathways originating from the CVOs to the hypothalamic PVN and to the RVLM and the NTS in the brainstem play an important role in the neurogenic hypertension [240,241]. Especially high level of AT1R expression is found in the SFO [239], and the SFO neurons are strongly activated by Ang II after occlusion of the renal artery in rats [242] and in response to chronic peripheral infusion of Ang II resulting in hypertension in rabbits [243]. Lesion of the SFO reduces arterial blood pressure in renovascular hypertension in rats [244]. Furthermore, the SFO along with the carotid bodies plays an important role in sympathoexcitation and rise in blood pressure induced by intermittent hypoxia and Ang II/AT1Rs [87]. In addition to systemic RAS, locally synthetized Ang II from Agt in the SFO may participate in the pressor response and contributes to development of hypertension independently of systemic RAS [96]. Of note, chronic exposure to Ang II leads to gradual decrease in the SFO elevated activity; however, the downstream nuclei of the hypothalamus, including the PVN and the SON, maintain constantly increased

6. Brain RAS in cardiovascular regulation in hypertension

activity [243], indicating plasticity in the sympathoexcitatory pathways triggered by Ang II at the SFO level. Thus, AT1Rs in the SFO appear to play a critical role in the development and maintenance of hypertension. The AT1Rs in the AP are involved in resetting the vagal and sympathetic components of the arterial baroreflex to higher pressure values, as seen in hypertension [90], and lesions of the AP limit the hypertensive effect of chronically administered Ang II and development of high blood pressure in renin-dependent hypertension [245e249]. In this line, intracerebroventricular administration of Ang II, which allows for interaction of Ang II with CVOs, was shown to depress the baroreflex and to increase renal sympathetic nerve activity in rabbits, actions that were blocked by AT1R antagonist losartan [250]. However, some studies provided contradictory results indicating that the AP plays insignificant role in development of hypertension induced by Ang II [251] or high blood pressure in the SHR rat [252]. Similar to the action of Ang II in the AP, activation of AT1Rs in the NTS results in decrease in baroreflex sensitivity and potentiation of the peripheral chemoreflex [253,254]. The AT1R-mediated blunting of the baroreflex depends on the endothelial nitric oxide synthase (eNOS) and Gq proteinemediated activation of phospholipase C, resulting in release of calcium ions and formation of calciumecalmodulin complex [255,256]. Local inhibition of AT1Rs in the NTS prevents desensitization of the baroreflex by circulating Ang II independently of the CVOs, including the AP [257], and this effect involves vasculareneural signaling possibly mediated by AT1Rs-enhanced activity of eNOS in hypertensive rats [258,259]. However, the role of AT1Rs in the NTS is not only prohypertensive, as selective knockdown of rodent-specific AT1aRs in the NTS of hypertensive SHR rats was shown to exacerbate high blood pressure and was associated with increased markers of inflammation in the peripheral circulation [260]. In addition to arterial baroreflex desensitization, AT1Rs in the commissural NTS, the main relay of afferent signaling from the carotid bodies to the brainstem, contribute to elevation of the blood pressure in the renovascular hypertensive rats [261]. In addition to the NTS and CVOs, local stimulation of AT1Rs in the PVN and the RVLM leads to sympathoexcitation. Optogenetics of the PVN revealed a discrete population of AT1R-expressing neurons in the PVN that causes elevation of blood pressure [262]. Local inhibition of AT1Rs with losartan in the PVN reduces sympathetic activity and blood pressure in SHR rats [263]. Furthermore, AT1Rs in the RVLM contribute to high blood pressure in Dahl-salt-sensitive rats on high sodium diet [264] and SHR rats [265]. Local microinjections of AT1R antagonist candesartan decreases lumbar sympathetic nerve activity and blood pressure in SHR rats [266]. There is evidence that the pressor action of Ang II acting on AT1Rs in the RVLM of hypertensive SHR rats, but not in normotensive WKY rats, depends on phosphatidylinositol-3 kinase [38]. In contrast to AT1Rs, several lines of evidence show that AT2Rs in the brain mediate antihypertensive and sympathoinhibitory effects. Specifically, upregulation of AT2Rs in the NTS/DMV complex attenuates development of high blood pressure and desensitization of the arterial baroreflex in renovascular hypertension in rats

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[123] and improves the baroreflex function in primary hypertension, however, with insignificant effect on blood pressure [124]. Chronic intracerebroventricular infusion of MasR agonist compound 21 decreases sympathetic activity, restores baroreflex sensitivity, and lowers blood pressure in SHR rats [267], whereas intrabrain infusion of MasR antagonist exacerbates DOCA-salt hypertension in female rats [268]. In contrast to the depressor effects in the dorsal medulla and CVOs, it was found that AT2Rs in the PVN are involved in maintaining tonic RSNA, as their inhibition decreased RSNA [80]. The prohypertensive and sympathoexcitatory effects of AT1Rs and antihypertensive and sympathoinhibitory effects of AT2Rs have been linked to activation of the microglia and the neuroinflammation involving the cardiovascular centers [269], with release proinflammatory cytokines, including TNF and IL-1beta, via AT1Rdependent mechanisms, and AT2R-mediated antiinflammatory cytokine IL-10. In fact, increased TNF and decreased IL-10 levels in the brainstem have been reported in SHR rats [270], in renin-transgenic (mRen2) 27 hypertensive rats [205], and in rats with Ang II-induced hypertension [271]. This is in line with findings that chronic intracerebroventricular infusion of losartan, AT1R antagonist, or minocycline, inhibitor of microglial activation, restores arterial baroreflex sensitivity in rats with increased content of sodium ions in the cerebrospinal fluid [272]. Despite critical role of microglia activation in centrally mediated hypertension via Ang II, both AT1Rs and AT2Rs are predominantly expressed on neurons of the key cardiovascular centers, such as the PVN or NTS, but not on the glial cells [241]. Thus, accumulating evidence indicates that Ang II and AT1Rs reciprocally with proinflammatory cytokines wind up pressor and sympathoexcitatory responses [184,273e276]. Studies investigating the ACE2dAng-(1e7)dMasR axis in the brain have revealed complex and opposing effects on the cardiovascular system [225]. MasR for Ang-(1e7) was found in all relevant cardiovascular centers of the hypothalamus and the brainstem [62], and MasRs and Ang-(1e7) exert both sympathoinhibitory and hypotensive effects as well as sympathoexcitatory and pressor responses depending on specific cardiovascular center of the brain [225]. Prolonged systemic administration of Ang-(1e7) in aged mice with elevated blood pressure exerted hypotensive effect that was associated with reduced sympathetic outflow to the heart [277]. Also chronic intracerebroventricular administration of Ang-(1e7) acting via MasR decreases high blood pressure and improves arterial baroreflex sensitivity in the DOCA-salt hypertension in rats [278]. Similar effects were found in hypertensive renin transgenic (mRen2) 27 rats, in whom chronic intracerebroventricular infusion of Ang-(1e7) exerts hypotensive effect and improves baroreflex sensitivity. These changes are accompanied by improved cardiac remodeling and decreased expression of proinflammatory cytokine TNF, increased expression of the antiinflammatory interleukin 10 (IL-10), reduced activity of ACE, and downregulated AT1Rs and inducible NOS in the hypothalamus [205,279], suggesting that antihypertensive/sympathoinhibitory effects involve upregulation of interleukin 10 and downregulation of TNF. In this context, recently, it was reported that expression

6. Brain RAS in cardiovascular regulation in hypertension

of proinflammatory cytokine TNF is increased and antiinflammatory cytokine IL-10 is decreased in the brainstem of SHR rats [270]. In SHR rats, expression of ACE2 is reduced in the RVLM in comparison with normotensive controls, and lentiviral-mediated overexpression of ACE2 in the RVLM decreases arterial blood pressure [75,78]. Experiments in organotypic slice cultures suggest that the main cellular target for Ang-(1e7) are astroglia rather than neurons in the RVLM and that astrocytes from hypertensive SHR rats show reduced response to Ang-(1e7) [84]. In addition, targeted upregulation of ACE2 in the PVN also reduces blood pressure in rats with Ang II-induced hypertension [280]. These findings suggest that reduced expression of ACE2, decreased synthesis of Ang-(1e7), and reduced responsiveness of the target cells may contribute to hypertension. This is supported by findings that systemic overexpression of ACE2 prevents development of Ang II-induced hypertension or DOCA-salt-dependent hypertension [74,281]. In contrast to studies with ACE2 upregulation, inhibition of MasRs or administration of Ang-(1e7) into the cardiovascular center containing presympathetic neurons leads pressor and sympathoexcitatory effects. Specifically, there is evidence that Ang-(1e7) and MasR in the PVN contribute to sympathoexcitatory and pressor effects. It was reported that administration of MasR antagonist into the PVN in normotensive rats reduces renal sympathetic nerve activity [80]. These findings were further confirmed in rats with hypertension induced by high salt diet, in whom inhibition of MasRs in the PVN reduced arterial blood pressure, RSNA, and norepinephrine and also decreased oxidative stress and production of proinflammatory cytokines, indicating that Ang-(1e7) is involved in enhancing sympathetic activity and increasing arterial blood pressure [79]. Furthermore, blocking of MasRs in the RVLM decreases arterial blood pressure in hypertensive renin-transgenic (mRen2)27 rats with overexpression of the mouse renin Ren2 gene in brain with resultant increased Ang II and reduced Ang-(1e7) in the brainstem [81,282], which indicates a pressor effect of endogenously acting Ang-(1e7) in the RVLM. Moreover, chronic administration of Ang-(1e7) into the RVLM exerts pressor effect and abolishes circadian variations of blood pressure in normotensive rats [283], as well as sensitizes the cardiac sympathetic afferent reflex and increases sympathetic activity [284,285]. The endogenous Ang-(1e7) in the RVLM contributes to maintaining high blood pressure and increased renal sympathetic nerve activity, effects that were found enhanced in SHR rats [286,287] and in the renovascular hypertensive rats [285,288]. However, it should be noted that in contrast to experiments performed in rats, Ang-(1e7) administered into the RVLM at physiologically relevant doses had insignificant effects on blood pressure in rabbits [82]. Contrary to Ang-(1e7) actions in the PVN and the RVLM, microinjections of Ang-(1e7) into the NTS have depressor effect, and inhibition of MasRs in the NTS attenuates baroreflex sensitivity in normotensive rats, but has insignificant effect in hypertensive (mRen2)27 rats [81]. This suggests that endogenous Ange(1e7) has limited tonic effect on the arterial baroreflex in this model of hypertension. Similarly, Ang-(1e7) acting in the NTS has a hypotensive effect in both normotensive

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and hypertensive SHR rats; however, its effect on the baroreflex sensitivity was weaker in the hypertensive animals [289]. In summary, available evidence indicates that Ang-(1e7) in the CSF or the bloodstream, thus acting via the CVOs, has blood pressure-lowering effect. However, locally acting Ang-(1e7) and stimulation of MasR has site-specific effects, with pressor effects of Ang-(1e7) in the PVN and the RVLM, and depressor effects in the NTS. The available evidence indicates that the brain RAS is critically involved in pathogenesis of arterial hypertension. Numerous preclinical studies in various models of arterial hypertension show that classic RASs with Ang II acting via AT1Rs in the cardiovascular centers in the hypothalamus and the brainstem contribute to sympathoexcitation, withdrawal of the vagal activity to the heart, and alteration of cardiovascular reflexes manifested by blunting of the arterial baroreflex and augmentation of the peripheral chemoreflex. These changes can be counteracted by ACE2dAng(1e7)dMasR/AT2Rs; however, the cardiovascular effects of this arm of the RAS highly depend on specific site of action in the central nervous system.

7. Role of brain renineangiotensin in cardiovascular regulation in heart failure Heart failure, especially with reduced ejection fraction, leads to decreased cardiac output, which is compensated for by sympathoexcitation and excessive activation of the RAS, termed as neurohormonal activation [290]. Preclinical and clinical studies indicate that overactivation of the sympathetic nervous system in chronic heart failure is in great part driven by altered and enhanced activity of the RAS that involves increase in ACEdAng IIdAT1Rs signaling, and decreased ACE2d Ang-(1e7)dMasR axis and downregulation of AT2Rs in specific cardiovascular brain centers [77]. Profound sympathoexcitation in patients and animals with heart failure reciprocally activates the systemic RAS, which in turn further stimulates changes in the brain RAS via the CVOs and enhances sympathetic activity [77,291e293]. Altered expression of ACE, AT1Rs, ACE2, and MasR in the hypothalamus and the brainstem has been reported in several models of heart failure. Specifically, ACE is upregulated, and ACE2 is downregulated in the hypothalamus and the PVN, and in the medulla oblongata in the NTS and the RVLM in pacing-induced heart failure in rabbits [294]. Similar changes in ACE and ACE2 expression are found in the hypothalamus of dogs with pacing-induced heart failure [295]. However, in a rat model of high-output heart failure, ACE expression in cardiovascular centers is not different from healthy controls [296]. Increased binding of specific radioligand to AT1Rs in the cardiovascular centers of the brainstem, the PVN, and the SFO was found in high cardiac output heart failure in rats [296] and in the PVN of postinfarction heart failure rats [297]. Increased expression of AT1Rs was also found in the RVLM of rats with chronic heart failure [298] and in the brainstem nuclei in mice with

7. Brain RAS in cardiovascular regulation in heart failure

postinfarction heart failure [299,300]. In rats with postinfarction heart failure, autoradiography also revealed increased binding for ACE and AT1Rs in the SFO, the OVLT, the PVN, and the median preoptic nucleus [194]. Furthermore, expression of AT1Rs is increased in the PVN and the SON, but reduced in the AP and the NTS in the pacing-induced heart failure in sheep [301]. Also, increased expression of AT1Rs was detected in the hypothalamus of dogs with pacing-induced heart failure [295]. Contrary to the findings in heart failure sheep, expression of AT1Rs was increased in the NTS of postinfarction heart failure rats [302]. Furthermore, in heart failure, circadian variations of AT1R mRNA expression in the brainstem are lost, and this is accompanied by disruption of circadian rhythms of blood pressure, heart rate, and baroreflex sensitivity [300]; similar loss of dayenight variability of blood pressure is often seen in patients with chronic heart failure [303]. In addition to angiotensin receptors present in neurons [269], there is evidence that AT1Rs expressed in the astrocytes play an important role in sympathoexcitation in heart failure mice [304]. There is evidence that Ang-(1e7) and MasRs in the RVLM are involved in sensitization of the cardiac sympathetic afferent reflex and sympathoexcitation [284]; however, the evidence on the role of Ang-(1e7) and its receptor in the RVLM in heart failure is limited. However, virally mediated overexpression of ACE2, the key enzyme in generation of Ang-(1e7), in the PVN, reduced sympathetic activity in chronic heart failure rats, and this involved increased expression of neuronal NOS [305]. In this line, exercise training in rabbits with pacing-induced heart failure upregulates ACE2 in the PVN and brainstem structures [294]. In addition, in rats with postinfarction heart failure, concentration of Ang-(1e7) and expression of MasRneuronal NOS axis are reduced in the dorsolateral periaqueductal gray, and this is associated with increased activity of neurons presumably involved in sympathoexcitation [306]. Furthermore, in mice with postinfarction heart failure, braintargeted overexpression of ACE2 resulted in decreased sympathetic activity, enhanced baroreflex sensitivity, decreased expression of AT1Rs in the brainstem, and improvement in cardiac hemodynamics manifested by reduction in the left ventricle diastolic pressures. These effects involved Ang-(1e7) and MasR, as peripheral chronic administration of MasR antagonist limited the positive effects of ACE2 overexpression [299]. In addition to Ang-(1e7) and MasRs, stimulation of AT2Rs counterbalances the sympathoexcitatory effets mediated by central AT1Rs. AT2R knockout mice experience increased mortality and exacerbation of heart failure after coronary artery ligation [307]; however, the brain-specific effects of AT2R in heart failure are not well delineated. Available evidence indicates that downregulated expression of AT2Rs in the RVLM contributes to exaggerated sympathoexcitation [298]. Furthermore, chronic intracerebroventricular administration of AT2R agonist compound 21 improves baroreflex sensitivity and attenuates sympathetic outflow in heart failure rats [308]. The functional meaning of altered brain RAS in heart failure has been further confirmed in pharmacological and lesion studies. In sheep with pacing-induced heart

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failure, intracerebroventricular infusion of AT1R antagonist losartan significantly and selectively reduces activity in cardiac, but not renal sympathetic nerves [301]. In the same model of chronic heart failure, lesion of the AP or intracerebroventricular administration of losartan causes significant reduction in the cardiac sympathetic nerve activity [88] and suppresses plasma vasopressin concentrations and improves hemodynamic status of the left ventricle [309]. Together, these findings indicate that sympathetic outflow is distinctly regulated to specific vascular beds and organs, and this involves brain RAS. There is also evidence that blocking the brain RAS normalizes hemodynamic response to stress stimuli in rats with postinfarction heart failure. Specifically, systemic administration of ACE inhibitor captopril or intracerebroventricular infusion of AT1R antagonist losartan normalizes augmented pressor response to acute stress [187,190]. Furthermore, the central AT1R-dependent attenuation of the pressor response involves vasopressin V1a receptors [187,195]. Inhibition of AT1Rs by local administration of losartan into the NTS reduces sympathoexcitation and attenuates enhancement of the peripheral chemoreflex by cardiac sympathetic afferent reflex [302]. In addition, the peripheral chemoreflex is augmented by stimulation of AT1Rs in the carotid bodies in rabbits with pacing-induced heart failure [115]. Thus, it appears that in heart failure the peripheral chemoreflex that drives sympathoexcitation is enhanced at the peripheral and central levels by Ang II and AT1Rs. Recently, it has been acknowledged that in heart failure the sympathoexcitatory effect of brain RAS involves development of neuroinflammation in the central nervous system [310]. Former studies have shown that in heart failure rat, AT1Rmediated sympathoexcitation involves activation of proinflammatory mediators and transcription factor NF-kB in the PVN [297,311]. Furthermore, regulation of blood pressure by AT1Rs depends on centrally acting endogenous TNF, and the cytokine potentiates pressor effect of centrally acting Ang II in rats with postinfarction heart failure [312,313]. This is further corroborated by findings that sympthoexcitation is accompanied by increased expression of Toll-like receptor 4 (TLR4) in the brain and reversed by intracerebroventricular administration of AT1R antagonist losartan in mice with postinfarction heart failure [314]. Also, several studies point to the association of upregulated AT1Rs and enhanced oxidative stress in the PVN and brainstem in driving sympathoexcitation and attenuation of baroreflex [292,297,300]. In conclusion, the brain RAS plays an important role in sympathoexcitation and is significantly altered in heart failure. Increased expression of ACE and AT1Rs in cardiovascular centers of the brain drives sympathoexcitation, attenuation of the arterial baroreflex, and augmentation of the peripheral chemoreflex. These responses are further enhanced by decreased expression of the ACE2dAng-(1e7)dMasR and AT2Rs. Targeting specific components of the brain RAS has been shown effective in alleviating autonomic imbalance in various models of heart failure.

8. RAS in diabetes mellitus and metabolic syndrome

8. Renineangiotension system in diabetes mellitus and metabolic syndrome RAS cooperates with endocrine systems regulating metabolism and energy balance, and its activity is significantly altered in metabolic diseases, especially in diabetes mellitus, insulin resistance, and the metabolic syndrome [315e318]. Hitherto studies analyzing the involvement of RAS in the regulation of metabolism and energy balance concentrated mainly on the role of peripherally acting angiotensins and allowed to consolidate a conviction that an excessive activation of RAS may cause significant impairment of metabolism [315,319,320]. Particular attention has been given to interaction of angiotensins with insulin and other hormones [318,321e323]. Recently, evidence emerges that the brain RAS may play a particularly important role in maintenance of energy balance through its engagement in the regulation of activity of the autonomic nervous system and release of other hormones affecting metabolism and food intake [324,325]. Angiotensinogen-deficient transgenic rats [TGR(AsrAOGEN)] maintained on high-caloric diet do not develop obesity in contrast to their Sprague Dawley counterparts fed the same diet. In the same study, chronic ICV infusion of Ang II prevented development of obesity during high caloric intake by decreasing food intake and increasing energy expenditure. The authors suggested that enhanced stimulation of Ang II receptors in the brain of [TGR(AsrAOGEN)] could possibly account for disturbances in energy homeostasis of these rats [325]. Neurons of the SFO, which have multiple connections with several brain regions controlling the autonomic nervous system, are sensitive both to glucose and to Ang II, which indicates that changes of glucose concentration in the SFO may interact with Ang II at the cellular level [326]. Studies attempting to determine regions of the brain involved in the regulation of energy balance by angiotensins draw attention to the PVN, the arcuate nucleus, and the circumventricular organs. In the streptozotocin-induced diabetic rats (STZ-DI), microinjections of Ang II into the PVN induced significantly greater increases in renal sympathetic nerve activity (RSNA), and pressor and tachycardic responses than in the control rats. Moreover, application of losartan or overexpression of superoxide dismutase into the PVN produced significantly greater decreases of these parameters in the STZ-DI rats than in the control rats. The STZ-DI rats manifested also significantly higher expression of AT1R mRNA and protein and greater expression of NAD(P)H oxidase subunits [(p22(phox), p478(phox), and p67(phox)] in the PVN than the control rats [327]. It is very likely that the arcuate nucleus of the hypothalamus may also participate in the regulation of energy balance by the brain RAS [328]. This nucleus is in close relations with the SFO and expresses prorenin and prorenin receptors, angiotensin AT1Rs, and MasRs for Ang-(1e7). It is also involved in the control of sympathetic activity and resting metabolic rate [237,317,329e331]. Systemic application of Ang-(1e7) was found to improve insulin sensitivity in aged mice [277]; however, chronic ICV infusion of this peptide was less effective in preventing development of obesity in rats maintained on high caloric intake than administration of Ang II [325].

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The adipose tissue may be another platform of interaction of the sympathetic nervous system with components of RAS [332,333]. The paraventricular nucleus is a source of presympathetic neurons innervating the adipose tissue, and the latter expresses local RAS actively participating in the regulation of energy balance [333,334]. In conclusion, it can be stated that the brain RAS plays an essential role in the regulation of energy balance, and that its function is significantly affected in diabetes and metabolic syndrome. The hypothalamic components of the RAS appear to be actively engaged in these processes; however, further studies are needed to determine more closely other putative connections of the brain RAS with the regulation of metabolism.

9. Renineangiotensin system in pathogenesis and outcome of myocardial infarction 9.1 Renineangiotensin system and the atherosclerotic plaque

Myocardial infarction, a clinical manifestation of ischemic (coronary) heart disease, is the main cause of mortality worldwide. According to the Global Burden of Disease (GBD) Study, 9 millions of deaths are caused by ischemic heart disease annually [335]. In Europe, ischemic heart disease (a subgroup of cardiovascular diseases) is responsible for 20% of all deaths [336]. Therefore, knowledge about pathophysiology of myocardial infarction is of utmost importance. Myocardial infarction is a consequence of atherosclerosis. Briefly, some atherosclerotic plaques become vulnerable and prone to be ruptured by the bloodstream. The thrombus generation upon ruptured plaque results in acute ischemia and subsequent necrosis of myocardial tissue [337,338]. Necrotic fragment of myocardial tissue is cleaned by macrophages and inflammatory cells and finally converted to fibrotic scar tissue. Scar has no ability to contract like myocardium, so the entire heart is subjected to the process of remodeling, which has a negative impact upon heart performance in a long-term perspective and may lead to chronic heart failure development [339]. In all the processes mentioned dplaque destabilization, necrotic tissue reorganization, and postinfarctional heart muscle remodeling, the RASs (both systemic and local) play an important role through its direct action on the heart, by regulation of blood volume and blood pressure (see before) and through the central regulation of the autonomic nervous system (see before) [340,341]. Angiotensin II is an active agent, which activates metabotropic AT1Rs on different tissues (especially in smooth vascular cells), causing contraction of the arterioles and increase of total peripheral resistance [342]. AT1 receptors localized within the heart promote intracellular pathways that lead to the cardiomyocytes hypertrophy [343]. Moreover, local RASs (brain, renal, and cardiovascular) cooperate with each other both in regulation of cardiovascular functions under physiological conditions and in pathogenesis of hypertensionda risk factor of myocardial infarction and heart failure (Fig. 2.2).

9. RAS in pathogenesis and outcome of myocardial infarction

FIGURE 2.2 Cooperation of the brain renineangiotensin system (RAS) with the cardiovascular RAS and the renal RAS. AVPdarginine vasopressin; [,Y activation or inhibition of functions regulated by systemic and local RAS in hypertension and heart failure.

The principal cause of myocardial infarction is atherothrombosis, i.e., thrombus generation upon ruptured atherosclerotic plaque, coronary artery stenosis or even total occlusion, and subsequent myocardial ischemia and necrosis. Atherosclerotic plaques prone to rupture present specific phenotypedthin fibrous cap (thickness of plaque 65 years). Arterial stenosis may progress over time triggering oxidative stress, proinflammatory cytokine release, and fibrotic cascades. Also, fibromuscular dysplasia (FMD), another idiopathic and noninflammatory disease, accounts for approximately 10% of cases of renovascular hypertensive and nearby 5.8% of secondary hypertension usually seen in women [44,45]. Another minor cause of generalized renovascular hypertension is traumatic renal artery or thrombosis in the kidneys due to antithrombin deficiency, which can occur after renal transplantation [46]. Renal damage in a hypertensive state appears to be influenced by other factors including age, dyslipidemia, atheroembolic diseases, etc.

3.1 Pathophysiology of renovascular hypertension Kidneys execute an intermediate role in the acceleration of mean arterial blood pressure. The sustained elevation in blood pressure is mainly characterized by vasoconstriction, fall in renal perfusion pressure, and resultant hypersecretion of renin via macula densa cells localized in juxtaglomerular cells in kidneys, which mediate the activation of RAS [47]. Noteworthy, the animal models of vascular diseases have played an outstanding role in scrutinizing the pathophysiological mechanisms of renovascular hypertensive disease [12]. This was pioneered experimentally long back in the 1930s when pathologists Goldblatt and Loesch observed the raised blood pressure upon reducing the renal blood flow in the canine model (now replaced by smaller animals) using three different approaches [48]. The constriction of both the renal arteries leads to the ischemic phase followed by the release of renin and angiotensin II referred to as the two-kidney two-clip model; thereafter, a twokidney one-clip model (2K1C; unilateral angiotensin-dependent renohypertensive model) in which clipped kidney secretes renin in response to lowered perfusion. In contrast, the contralateral kidney exhibits natriuresis due to higher perfusion pressure. In the second model, one-kidney one-clip process (stenosis of solitary kidneyvolume dependent model) involves the removal of contralateral kidney and remnant kidneys undergoing artery constriction. Initially, renin is secreted in the early phase due to low renal arterial pressure. Later, this model leads to volume expansion in stenotic kidneys due to no compensation offered by the alternative kidney that ultimately decreases the renin secretion, and no natriuresis takes place [49,50]. In general, humans correspond to the 2K1C model where the amount of renin is exclusively high. However, it is conflicting whether the one-clip one-kidney model relates to bilateral RVH in humans; nevertheless, there is mounting evidence suggesting both renin and volume factors trigger hypertensive condition. Later, Guyton and Hall in the 1980s stated that kidneys can influence cardiac output plus blood volume causing an elevation in blood pressure due to both sodium and volume retention [51].

3. Renovascular hypertension

Notably, it is known that nNOS and COX-II enzymes are constitutively expressed in macula densa cells and hypersecretion of renin is mediated by upregulation in these enzymes [52]. The bioavailability of the defensive vasodilator nitric oxide (NO) is strongly dependent on redox status, and ROS has been linked to a decrease in eNOS bioavailability, which can affect endothelial function [53]. There is mounting evidence that the generation of ROS acts as primary mediators to directly cause endothelial dysfunction manifested due to exacerbated vascular oxidative burst contributing to deleterious effects on RVH. In the early stage of renovascular hypertension, upregulation in plasma renin activity contributes to the amplification of systemic oxidative stress. NADPH oxidase is a predominant enzyme present in vascular layers that participate in the generation of reactive oxygen species [50]. The homologs of NADPH oxidase are broadly referred to as NOX enzymes, although NOX family comprises many isoforms NOX2 (also called gp91phox subunit) is mainly involved in the initiation of oxidative burst (generation of superoxides OL 2 ) underlying renovascular hypertension [54]. Interestingly, renin production and enhanced angiotensin II release have been documented to activate gp91phox containing NADPH oxidase by mediating superoxide production and generating mitochondrial ROS leading to endothelial dysfunction [55,56]. Considering the physiological conditions, low intracellular levels of ROS constitute a unifying mechanism in the regulation of normal redox status and hence integrity and vascular function. In the vascular wall, NADPH oxidase activation originates reactive oxygen species, leading to tubular hypertrophy, injury to podocytes, and tubulointerstitial injury [57]. The upregulated expressions of adhesion molecules (ICAM-1, VCAM-1, and selectins) actuate the recruitment of leukocytes superficially on mesangium, vascular smooth muscle cells, and endothelial cells. The high peak of angiotensin II exacerbates the adhesion of leukocyte and endothelial cell by activating AT1 receptors [53]. It is also worth mentioning that renovascular hypertension is integrated with chronic inflammatory state signified by increased vascular permeability, precipitation of macrophage infiltration, upregulation in NGAL levels [58], MCP-1, IL-6, TNF-a, TGF-b1, and increased synthesis of collagen types I and III causing fibroblast proliferation [59,60]. Increased renal sympathetic signaling due to adrenergic overactivity in kidneys and vasculature itself has also been found to potentially facilitate the increase in renin activity, leading to increased blood pressure and simultaneous risk for cardiovascular dysfunction. Activation of sympathetic renal nerves upgrades tubular reabsorption of sodium ions and renal vascular resistance via AT1 receptor activation [61,62]. Moreover, oxygen consumption is a major determinant of tubular sodium reabsorption in kidneys. The presence of reduced renal oxygenation followed by tissue hypoxia in an experimental model of renovascular hypertension was reported by Welch et al. in 2005. Certainly, the restoration of renal oxygenation in hypertensive kidneys can intercept the progression of renal oxygenation-related defects in nephrons [63]. Over and beyond, the pharmacological inhibition of RAAS can mitigate the upregulated NADPH oxidase activity and also directly blunt the sympathetic stimulationmediated renin release from JG cells, thus preventing or retarding the inflammatory

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processes in the development of chronic kidney diseases associated with RVH. It is widely accepted that suppression of RAAS using ARB/ACE constitutes the first-line therapy in renal insufficient patients [64].

3.2 Role of angiotensin II in renovascular hypertension The peptide hormone angiotensin II (Ang II) is acknowledged to be a regulating factor in the pathogenesis of renovascular hypertension [65]. The Ang II reduces blood flow in kidneys and mesangial surface area (this causes a marked decrease in process of filtration) and increases in glomerular capillary pressure (this increases the filtration) [42]. It is well known that NADH/NADPH oxidase system is crucial for the development of O 2 in endothelial cells, mesangial cells, and VSMCs [66,67]. In an investigation, Griendling and Minieri showed that angiotensin II is an important factor to stimulate NADH/NADPH oxidase in VSMC and mesangial cells via AT1 receptor binding [66]. For the reason that AT1 receptor functions through G protein adenylate cyclase, phospholipase C, and IP3/DAG pathways, this eventually leads to upregulation of calcium levels intracellularly that activates PKC signaling transduction [6,7]. Since the NADPH-dependent oxidase activation is a PKC-dependent pathway, the authors observed that increased angiotensin II release and superoxide production are integrated by PKC signaling in the 2K1C model of hypertension in rats. It has been observed that unilateral renovascular hypertension precipitates massive proteinuria due to the lesions of focal segmental glomerulosclerosis along with the presence of arterial smooth muscle cell hypertrophy in the contralateral kidney [67]. In addition, it is reported in the literature that angiotensin II stimulates PKC a-dependent NADPH oxidase responsible for superoxide production via AT1 receptor activation inside the thick ascending loop of Henle [68]. The glomerular filtration barrier is composed of podocyte foot processes with three layers of cellsd endothelium, glomerular slit diaphragm, and glomerular basement membrane Furthermore, angiotensin II tends to promote extracellular matrix deposition and constricts the mesangial cells leading to reduced availability of glomerular surface area for filtration. Perhaps the glomerular mesangium hypertrophy/hyperplasia has also been implicated in the progression of glomerulosclerosis among RVH cases [69,70]. Previous studies have addressed that angiotensin II mediates the podocyte injury and causes albumin leakage via AT1 receptors by activation of Src kinasephospholipase C. Moreover, the Ang II increases the endocytosis of nephrin (this is an intrinsic part of the glomerular slit diaphragm) that further alters the structural integrity of the podocyte junction enhancing the glomerular permeability [15]. The expansion of mesangial cells has been associated with increased expressions of TGF-b that contribute toward the synthesis of matrix and may present the worsening of kidney disease [71]. Notably, AT1R is localized on the immune cells (lymphocytes, monocytes, dendritic cells, as well as macrophages), and its stimulation by angiotensin II can induce differentiation of immune cells and proinflammatory cytokine production. Additionally, P-selectins and other adhesion molecules also affect the invasion and migration

3. Renovascular hypertension

of leukocytes by increasing AT1R expression [72]. Regardless of vasoconstricting actions of angiotensin, the clotting system can be influenced by angiotensin [73]. Several in vitro evidence also affirmed the occurrence of thrombus formation with the release of angiotensin II. The authors investigated the prothrombotic features of Ang II and its analogs Ang III and Ang IV on venous thrombosis, coagulation, and fibrinolytic systems underlying renovascular hypertension in rats. It was noted that angiotensins II and IV considerably caused an increase in thrombus formation via acting on AT1 receptors; however, angiotensin III did not play any significant role in the process. These pathological changes were related to augmented adhesion of leukocytes, fibrin formation, and expression of Pai-1, which are particularly important in physiological blood clotting events and also implicated in fibrotic actions [74]. Furthermore, Johnson et al. uncovered the parallel association of focal tubular injury in angiotensin-mediated hypertension [75]. In this study, angiotensin II infusion in rats induced tubular dilatation, tubular atrophy, interstitial fibrosis, and cast formation accompanied by the migration of monocytes in the interstitium and increased deposition of type IV collagen in rats. In angiotensin-treated rats, smooth muscle hypertrophy and hyperplasia were seen in blood vessels, as well as actin upregulation by mesangial cells and increased desmin by visceral epithelial cells in the glomerulus [75]. This is noteworthy that the local physiological role of systemic RAS and intrarenal is independent of each other [76]. In this view, a study checks intrarenal levels of ACE2 and neprilysin and their urinary excretion in 2K1C hypertensive mice. ACE2 is the potent renoprotective enzyme responsible for the transformation of Ang I into Ang 1-9, which counteracts the vasoconstrictive effects of angiotensin II. In addition, declined ACE2 activity has been implicated in inflammatory conditions and glomerulosclerosis. In a study, hypertensive rats were developed using the 2K1C approach in rats that displayed albuminuria, reduced urinary and intrarenal levels of neprilysin, and ACE2 enzyme. It was observed that the AT1R deletion prevented albumin excretion yet did not influence renal ACE2 and neprilysin expressions suggesting a lack of interaction between both [77]. Generally, granulocyte colony-stimulating factor (GCSF) serves as a regulating facet secreted from kidneys for proliferation and differentiation of hematopoietic cells and is therapeutically favorable against neutropenia. It has already been documented in experimental studies that GCSF ameliorates apoptosis, renal inflammation, and fibrosis in ischemic kidneys. In another study, the protective role of GCSF in a murine model of 2K1C angiotensin-dependent hypertension was investigated. As anticipated, the plasma angiotensin levels were found to be increased in hypertensive mice. Also, morphological alterations manifested as collagen deposition in glomerulus and atrophy were evident in 2K1C-subjected mice. Notably, the administration of GCSF reduced the rise in angiotensin II levels and potentially ameliorated the morphological alteration in renovascular hypertension [78]. Welch et al. (2005) examined the involvement of oxidative stress and superoxide anion O─2 -induced renal oxygenation defects in intact kidneys of angiotensin II-induced hypertensive rats. The prolonged angiotensin II infusion in these rats enhanced renal cortical superoxide levels

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resulting in hypoxia in the renal cortex and reduction in efficiency of oxygen for Na transport. However, coadministration of SOD mimetic tempol (superoxide scavenger) prevented these angiotensin II-mediated renal oxygenation defects indicating the major pathological involvement of oxidative stress in the development of angiotensin II-dependent hypertension and renal hypoxia. The rodent model of 2K1C Goldblatt hypertension also exhibits renal oxygenation defects similar to angiotensin II-induced hypertension. The low perfusion pressure and increased angiotensin II in these rats manifested angiotensin II-dependent hypertension and displayed enhanced oxidative stress intrarenally. The number of oxidative mediators was found to be significantly increased along with the decline in oxygen efficiency for Naþ transport and low renal cortical oxygen tension (PO2) in the 2K1C model. However, lowering of blood pressure by administration of SOD mimetic tempol partially corrected renal cortical hypoxia and improved oxygen efficiency in the clipped kidney of this model [63]. Importantly, endothelial to mesenchymal transition (EMT) is a known mediator of fibrogenesis in kidneys. There have been several previous studies concerning EMT in renal dysfunction. In the recent past, Lin et al. addressed the impact of endothelial-to-mesenchymal transition and renal fibrosis among angiotensininduced hypertensive rats [79]. In this study, an angiotensin-induced hypertension model was employed to investigate the interplay of EMT-related pathological mechanisms that cause hypertensive renal dysfunction. Emerging evidence reveals that Sirtuins (Sirt3) localized in the mitochondrial matrix confers protection against various inflammatory cascades and its depletion is associated with distinct renal pathologies [80]. The authors observed the significant downregulation of Sirt3 in the hypertensive kidneys that in turn mediates EMT along with reduced catalase expression, high oxidative stress, and fibrotic cascades. However, in Sirt3 overexpression transgenic mice, all these manifestations were retarded suggesting the renoprotective role of Sirt3 in angiotensin II-mediated hypertension. FOXO3 is a protein that participates in vascular homeostasis and its downstream is implicated in vascular diseases [81]. In the same study, in knockout mice of Fox03, all the pathological alterations again appeared back. Thus, the study marks the prevention of hypertension in relation to the importance of the Sirt3-Fox04 pathway in the maintenance of EMT and endothelial homeostasis [79]. The relationship between centrally acting angiotensin II and noradrenergic neuroeffector junction has also been evaluated in the clinical study earlier and indicated that RVH accelerates noradrenergic transmission depending upon noradrenaline release [82,83].

3.3 AT2 receptor activation in renovascular hypertension Several effects of the AT1 receptor are opposed by the AT2 receptor by promoting vasodilation and preventing cellular differentiation and proliferation [7]. In a study, the role of AT2R stimulation was evaluated in response to early inflammatory cascades in the 2K1C Goldblatt hypertensive model. As anticipated, clipped kidneys released the proinflammatory mediators, which include TNF-a, IL-6, and TGF-

4. Atheromatous renovascular disease

b1, and lowered the levels of renal NO and cGMP, respectively. AT2R agonist administration stimulated the AT2R expressions in the hypertensive animals and downregulated the inflammatory process in kidneys and improved NO and cGMP signaling causing relaxation and vasodilatory actions. Nevertheless, no change in blood pressure upon treatment was reported in the investigation [84].

4. Atheromatous renovascular disease Atheromatous renovascular disease (ARVD) is known as a systemic syndrome, mainly linked with aging, chronic renal disease, smoking, diabetes, and hypertension including hyperlipidemia [85e89]. It is also highly associated with ischemic and congestive heart failure, and also with peripheral as well as cerebrovascular diseases [90]. It is estimated that the prevalence of ARVD is 7% in the elderly. Moreover, its prevalence is 30% in patients with CHF, 10% in patients with coronary artery disease, 10% in stroke patients (10%), and also 10% in CKD patients [91]. According to Medicare data, ARVD patients have a threefold increased risk of death compared with non-ARVD patients [85]. Moreover, it is also reported that the annual mortality rate of ARVD patients receiving dialysis is 36% [86]. Medically, atheromatous (atheromas) is defined as the buildup of materials or plaque that accumulate in the arteries with time. This buildup makes the arteries narrow and hardened with plaque, thus obstructing the blood flow, and such a condition is also known as atherosclerosis. Atheromatous may occur after repeated injury in the endothelium, which is accompanied by inflammation. In response to this injury, foam cells are formed, which attract fats and cholesterol, thereby promoting the growth of atheromas [91]. Fig. 5.2.

4.1 Pathophysiology of ARVD ARVD results in lowering of blood flow and renal artery pressure, which causes adverse parenchymal injury and also activates the renin release, thus increasing the angiotensin and aldosterone production [92,93]. Luminal obstruction-dependent renal arterial diameter modification leads to hemodynamic changes. Normally, kidneys are subjected to more blood and oxygen delivery in comparison with that needed for metabolic demands. When the ARVD is very severe, the kidneys suffer from reduced renal blood flow for a prolonged period. Furthermore, there is a higher rate of perfusion in the cortex region, and the medullary regions have reduced blood flow due to more oxygen utilization for metabolic work and during solute transportation [94,95]. In spite of all these changes, kidneys can tolerate 30%e40% off subsequent reductions in the blood flow, which is unaccompanied by aggravation in the renal tissue hypoxia, and moreover, this is brought by a decrease in the renal filtration and its subsequent oxygen consumption [96]. Numerous studies have claimed that as a result of high-grade renal artery stenosis, there is a strong decline in renal blood flow, which also resulted in the development of cortical hypoxia.

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FIGURE 5.2 Pathogenic pathway in atheromatous renovascular disease (ARVD).

Moreover, this condition is accompanied by a decrease in the renal microvessel density, mitochondrial impairment, and the upregulation of tissue inflammatory pathways, which also triggers oxidative stress and cellular infiltration in the renal tissue. With time, inflammation will further promote fibrosis, and also nephron loss. Thus, the progressively reduced kidney function becomes irreversible despite the renal blood flow restoration [97].

4.2 Angiotensin II in progression of ARVD Angiotensin II produces its effect by binding with the angiotensin receptors (both type 1 and type 2) [98]. It has also been observed that in the endothelium, Ang II on binding with type 1 receptor produces elevated Ca2þ concentration within the endothelial cells, which directly promotes endothelial dysfunction via generation of ROS, which is derived most abundantly from NADPH oxidase [99]. Inflammation and oxidative stress conditions in atherosclerosis are accompanied by elevated Nox5 (a known member of NADPH oxidase) found in the vascular cells, including resident macrophages [100]. This Nox5 activated by Ang II further acts as a stimulus for superoxide anions (O 2 ) release and subsequent activation of the RhoA/ROCK

4. Atheromatous renovascular disease

pathway. This pathway is the key activator of protein kinases (p38 MAPK and ERK 1/2), further mediating the various transcription regulator such as NF-kB [100,101]. Moreover, NF-kB is the regulator of several gene expressions including that of cytokines, TNF-a, IL-6, chemokines, adhesion molecules, and also inflammatory enzyme COX-2 and angiotensinogen [102]. It has been observed that the stimulation of Ang II upon binding with type 1 receptor further promotes the release of TNF-a and chemokines along with adhesion molecules in the arterial endothelial cell [101]. Ang II also induces macrophagic apoptosis, leading to atherosclerotic plaque vulnerability in the renal tissue via AMPK/p38 MAPK pathways [103]. Additionally, Ang II also enhances the level of osteopontin in the renal epithelial and endothelial cells, including macrophages. Osteopontin is a multifunctional protein discovered in a variety of atherosclerotic lesions, including macrophages (also lipid-laden macrophages), implying that it plays an important role in the genesis and progression of atherosclerosis [104]. Furthermore, Ang II increases the LOX-1 gene expression, a receptor for the oxidized form of LDL [105]. The binding of oxidized LDL and LOX-1 within the renal endothelium can induce endothelial dysfunction through the stimulation of apoptosis pathways and also increase the generation of ROS and leukocyte adhesion molecules [106]. However, oxidized LDL can also mediate the development of Ang II through increasing the production of angiotensinconverting enzyme, this Ang II, in turn, upregulates the expression of LOX-1 which further leads to self-attributing proatherogenic cycle. Furthermore, the research has suggested that angiotensin-converting enzyme inhibitors and type 1 receptor blockers can suppress LOX-1 expression and so have renoprotective effects [105] (Fig. 5.3).

4.3 Role of ACE-I/ARBs (ACE inhibitors/angiotensin receptor blockers) in ARVD Several findings have suggested the renoprotective activity of ACE-I/ARBs; it is considered as the first-line drug for therapeutic treatment of hypertensive renal diseases [106]. In ARVD conditions, even a low dose of ACE-I/ARB is sufficient to bring improvement in the blood pressure, for which several other antihypertensives have failed to do so [107]. In terms of tolerance, they are better than several other antihypertensives, thereby promoting the withdrawal or dose reduction of such antihypertensive drugs, which are having very poor or no efficacy, and are poorly tolerated [108]. Apart from hypertensive effects, the use of ACE-I/ARB is suggested to be renoprotective in CKD patients [109]. In ARVD, the patients often suffer from atherosclerosis and other cardiovascular-related complications, and therefore, treatment with ACE-I/ARB can be beneficial for the ARVD patients in multiple ways. One of the most common beneficiary outcomes is in the reduction of proteinuria, which is a potential biomarker of renal dysfunction [110,111]. However, the use of ACE-I/ARB can have some adverse effects including hypotension, renal insufficiency, and high level of potassium in the blood, which can be anticipated by

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FIGURE 5.3 Angiotensin and the development and progression of atheromatous renovascular disease (ARVD).

maintaining conventional titration of doses and subsequently checking the renal functions postadministration and after each dose increment [112].

5. Ischemic renovascular disease Jacobson in 1988 designated ischemia nephropathy as the reversible renal injury due to narrowing of the renal artery [113]. The hemodynamically altered renovascular obstructive disease is characterized by altered circulatory volume, renal hypoperfusion, consequent fall in the amount of plasma filtered or GFR, luminal obstruction with cellular debris, and damaged renal parenchyma tissue progressing toward ischemic nephropathy [114]. In patients, autopsy-related studies revealed an 18% incidence of IRD in the aged population between 64 and 75 years, which increases by 42% among the older age group [114]. In the previous report, Fatica et al. documented the prevalence of overt IRD leading to ESRD by the net rate of 12.4%, which is much more than the other causes of ESRD including all-cause ESRD (5.4%) and diabetes (8.4%) [115]. Restoration of renal blood flow by surgical or endovascular methods can prevent progressive disease and sometimes improves renal function. However, clinical studies commonly indicate that some patients lose further kidney

5. Ischemic renovascular disease

function after revascularization [116]. This may be explained partly by undetected renal atheroemboli or other injuries related to vascular repair procedures. Both hypertension and renal insufficiency are the predominant clinical manifestations of ischemia nephropathy [117]. Renal ischemia coexists with renal artery stenosis often in the condition occurring with renin-dependent hypertension [118]. Hemorrhage, prolonged vomiting, and sweating also lead to ischemic acute tubular injury [119].

5.1 Pathophysiology Ischemia impairs the autoregulatory mechanism in kidneys. In spite of the complex mechanism behind acute renal failure, the existence of stenosis inflicts ischemia nephropathy in an independent manner [120]. It has been well understood that a key feature of ischemic nephropathy pathogenesis is actually linked to the diminished medullary flow of blood and inadequate delivery of oxygen to the tubular zones of the nephron, resulting in cellular injury due to dyshomeostasis between oxygen supply and demand [121]. The complex interaction between congestion in medullary vasculature and tubular injury results in signaling cascades such as leukocyte accumulation that causes damage to tubular epithelial cells [122]. It involves activation of coagulation pathways, fibrogenic cytokines, cytopathic modulation in organs, and mitochondrial dysfunction. Activation of oxidative stress and proteases within the nephron considerably plays a major role in continuing tubular damage. Notably, ATP is mainly required to generate apoptotic cascades, and due to limited mitochondrial ATP formation due to ischemic insult, there is lowered production of ATP in proximal convoluted tubules before injury [123]. Renal function recovery following reperfusion is dependent on restoring glomerular hemodynamics as well as proliferation and differentiation of cells, in the proximal tubule segments, which are more vulnerable to this type of injury [99].

5.2 Role of Angiotensin II in ischemia nephropathy It is observed that the activation of RAAS has a predominant involvement in the pathogenic causes of vascular injury, stenotic condition, and ischemia nephropathy. Even in acute conditions, renal ischemia can result in kidney damage manifested by tubular damage, interstitial fibrosis, and proteinuria including glomerulosclerosis [114]. Pagtalunan et al. (2000) examined the contribution of angiotensin II in tubular and glomerular changes by occlusion of the left renal artery and performing right nephrectomy in rats [124]. In this study, ischemia resulted in detachment of some tubules from glomeruli; however, remaining glomeruli were still connected to tubules and sclerotic or fibrotic lesions were manifested in both cases. Administration of enalapril in rats inhibited the injury in both cases. Although these results concluded that Ang II is not a cause for early tubular damage and fibrosis while healing from renal ischemia reperfusion injury; nevertheless, inhibition of Ang II can alleviate proteinuria and injury to glomerulus [124]. The previous data also indicate that renal ischemic injury in rats (60 min bilateral renal pedicle occlusion) results in

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elevated creatinine and intrarenal Ang II levels, accompanied by decrease in angiotensinogen mRNA expression in cortex and AT1 receptors at proximal tubular resulting in preservation of glomerular actions of Ang II that was furthermore completely inhibited by losartan treatment. Losartan administration decreased creatinine and initiated amelioration renal dysfunction, suggesting that in the postischemic kidneys, AT1 receptors activation deteriorate glomerular filtration. Osteopontin is a glycoprotein expressed in immune, bone, epithelial cells, smooth muscle, and endothelial cells, which are markedly involved in various pathological phases including those due to renal ischemia, obstructive injury, and drug-induced nephrotoxicity. It is also known to regulate angiogenesis, apoptosis, immune responses, and inflammation. The distinctive outcomes of angiotensin II infusion on renal function were evaluated in wild-type (WT) and osteopontin knockout (KO) mice. Angiotensin-treated WT and osteopontin KO mice exhibited sustained hypertension and elevated urinary albumin/creatinine ratio. However, only the kidneys of WT mice were manifested with macrophage infiltration, and also elevated levels of a-smooth muscle actin and TGF-b including fibronectin were observed. Nonetheless, in osteopontin KO mice, the expression of MCP-1, isoforms of NADPH oxidase such as NOX2 and NOX4 responsible for oxidative dysfunction, and plasminogen activator inhibitor1 were also significantly upregulated in comparison with WT mice. Cell culture studies have also been demonstrated that in proximal epithelial cells, osteopontin, and Ang II have upregulated the levels of a-smooth muscle actin and TGF-b. Notably, osteopontin antibody blocked these effects of Ang II in addition to alleviation of increased plasminogen activator inhibitor 1 expression. This study overall illustrates the dual role of osteopontin acting as both promoter and a blocker of fibrosis, oxidative stress, and inflammation, thereby suggesting its role in modulating angiotensin II-related renal injury [125]. Basil et al. (2012) reported in the past decade that Ang II acts nonhemodynamically as a multifunctional cytokine possessing various properties such as growth factor and profibrogenic cytokine, including some proinflammatory properties. Most of these detrimental functions in kidneys were modulated by TGF-b and other chemokines activated by Ang II. In the kidney, ischemic injury can lead to permanent damaged peritubular capillaries density by 30%e50% mediated by increased proteinuria and development of tubulointerstitial fibrosis and increased TGF-b expression [126]. These alterations explained that renal ischemia leads to long-term alterations in renal anatomy and physiology. Durvasula et al. (2004) investigated that mechanical strain leads to glomerular capillary hypertension, increment in Ang II production, and simultaneously upregulation of AT1R in podocytes. All of these variations have prompted a local angiotensin system, which has resulted in a significant increase in podocyte apoptosis mediated by AT1R [127]. However, the clinical significance of stretch-induced apoptosis linked to glomerular capillary hypertension such as podocyte degeneration and glomerulosclerosis remains to be elucidated in patients.

6. Diabetic nephropathy

6. Diabetic nephropathy The renal dysfunction due to complications of longstanding diabetes mellitus and poor glycemic control is so-called diabetic kidney disease. Sustained albuminuria, diminished GFR, and hypertension are general characteristics of DN. An increase in subclinical ARVD is a common complication in the onset of diabetes nephropathy [128]. In the 1980s, due to the lack of noninvasive techniques, it was quite inconvenient to produce epidemiological data for renal artery stenosis in patients suffering from diabetics [129]. However, renal arteries subjected to the MRA technique documented that renal artery stenosis accounts for 33% prevalence among diabetic subjects [130].

6.1 Pathogenesis of diabetic nephropathy In clinical diabetic kidney disease, the renin secretion in plasma is slow yet despite this, intrarenal levels of renin are significantly higher [131]. The pathophysiology of diabetic nephropathy involves the complex interplay of both hemodynamic (responsible for raising systemic and intraglomerular pressures, RAAS and endothelin pathways activation, increased vascular permeability) and metabolic features (advanced glycation products, oxidative stress, nephrin excretionepodocyte injury). The increase in mechanical strain from hemodynamic changes mediates the migration of certain cytokines and growth factors. These early modifications lead to renal hypertrophy and albuminuria from glomerular capillaries. This in turn causes morphological abnormalities in DN including GBM thickening, mesangium expansion, and glomerulosclerosis. Vascular, glomerular, and tubular lesions are central to the pathology of DN [132]. In context to RAAS, hyperglycemia is corresponding with the overactivation of angiotensin II. In a human study, renal biopsies from diabetic nephropathic patients depict that increases in both angiotensin II and ACE enzyme are implicated in the release of IL-1, IL-6, and IL-18, TNF-a, NF-KB along with MCP-1 responsible for provoking inflammation and fibrosis, and osteopontin in the tubular and interstitial regions of the nephron. Furthermore, the infiltration of monocytic cells and macrophage was also detected in response to DN patients with increased angiotensin levels [133,134]. The extensive use of ACE inhibitors and antagonists of angiotensin receptors for the management of cardiorenal dysfunction might predispose diabetics subjects to severe harm if they are in the state of renal artery stenosis [24].

6.2 Role of angiotensin II, ACE inhibitors, and ARBs in diabetic nephropathy The associated components of the RAAS especially angiotensin II significantly contribute to the genesis of diabetic nephropathy. There is accumulating clinical and preclinical evidence that has documented the renoprotection by ACE inhibitors and ARBs in the management of diabetic nephropathy. In an investigation on

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humans, it was speculated that in patients suffering from overt type 1 diabetic nephropathy, administration of ACE inhibitors reduces the incidence of chronic kidney disease and death rates compared with the patient non-RAAS cohort. In spite of identical blood pressure ranges observed among both the groups, renoprotection was conferred because of a decrease in proteinuria levels. The development of microalbuminuria can also be augmented by ACE inhibitors in hypertensive type 2 diabetic patients and in people with normal albumin excretion. This clearly indicates that the inhibition of RAAS also reduces the glomerular permeability toward albumin excretion. In addition, ACE inhibitors administration during the early phase of diabetic kidney disease results in cardioprotective effects. But ARBs show less cardioprotection and more therapeutic renoprotection in diabetes nephropathy patients and microalbuminuria [135]. In another clinical investigation, the simultaneous administration of ACE/ARBs remarkably diminished albuminuria in diabetic patients with minor effects on GFR, creatinine, and blood pressure [136]. This suggests that synergistic effects of ACE and ARB should be considered as compared with individual effects of these drugs. Angiotensin II is a known stimulator of NADPH oxidase that actively generates reactive oxygen species within nephrons. Therefore in a study, the deleterious role of oxidative stress in STZ-injected diabetic rats was evaluated. In this study, NADPH oxidase was found to be upregulated (determined by p47phox, a cytosolic component of NADPH expressed in leukocytes) in the glomerulus as well as tubules. Lipid peroxidation, albumin excretion, and the eNOS concentration were also markedly upregulated in diabetic rats in opposition to nondiabetics. Notably, treatment with ACE inhibitor and ARBs for a period of 2 weeks in STZ rats reversed these manifestations including improvement in albumin excretion and ameliorated oxidative stress mainly by downregulating the p47phox gene in diabetic kidneys. The current study suggests the pathological implication of the AT1 receptor in kidneys [137]. Likewise, in another randomized trial, the ACE inhibitors were administered to diabetic patients followed by different doses of ARB. This dual therapy resulted in synergistic effects by declining albumin excretion among hyperglycemic patients though showing no effects on blood pressure [138]. In contrast, an investigation by Maan et al. reported that combining ACE inhibitors and ARBs only prevents proteinuria; otherwise, it results in the aggravation of other renal outcomes. This study neglects the idea of synergism and the possibility of better results due to combination therapy [139]. Other RAAS inhibiting agents, including aldosterone antagonists and renin inhibitors, have also been studied for possible renoprotective benefits in renal insufficiency patients, either alone or in combination with ACE inhibitors or ARBs. Notably, in the separate study, the signaling of AT2 receptors and ACE2 was addressed in diabetic and nondiabetic kidney disease conditions. In this study, rats were subjected to ischemia reperfusion, and the parallel group was fed with streptozotocin to induce diabetes mellitus (DM) followed by ischemic reperfusion renal injury (IRI). As a result, an increase in plasma levels of Ang II, ACE1, and AT2R (along with AT1R) and reduced ACE2 in rats who underwent ischemia reperfusion

7. Conclusion

injury was noted. These IRI subjected rats also represented augmented renal apoptosis and inflammation. Notably, all these manifestations in ischemic kidneys were more prominently visible in STZ-administered rats. Both the respective groups were further coadministered with ACE activator and agonist of AT2 receptor that resulted in upregulation of ACE2 and AT2 receptor. This study demonstrated that AT2R and ACE2 activation are crucial to prevent not only IRI rats but also diabetic nephropathyesubjected IRI rats by ameliorating oxidative and inflammatory stress, improving tubular damage and apoptosis [140]. The beneficial effect of ARBs and ACE inhibitors is widespread and is not only limited to control of blood pressure. On this account, delays in the progression of glomerulosclerosis with ACE inhibitors and ARB are outlined in clinical and preclinical models of diabetic nephropathy and ischemia reperfusion damage. It has been postulated that glomerular cells are a direct target for Ang II to produce sclerosis irrespective of its hemodynamics and vascular actions since medicines that hinder the action of Ang II can reduce damage to the glomerulus without influencing glomerular pressures. Thus, to consider the nonhemodynamic actions of Ang II, cell culture techniques are employed on matrix metabolism by researchers. In culture, angiotensin and glucose displayed indistinguishable consequences on renal cells. For example, mesangial cells are incubated with either angiotensin II or high glucose mediates matrix protein synthesis and amelioration of plasmin activity and collagenase. In the nephron (proximal tubular region), the availability of glucose upregulates the expression of the angiotensinogen gene. Hence, Ang II levels are also enhanced in the cell culture of primary mesangial cells suggesting that a higher amount of glucose can itself stimulate the renineangiotensin system. Moreover, upregulated TGF-b levels are implicated in mediating the metabolism of a mesangial matrix under the influence of Ang II and glucose. Importantly, these alterations on the mesangial matrix can be prevented using antibodies of TGF-b and ARBs. Taking into consideration, these outcomes support the fact that hyperglycemia intensifies the release of Ang II from mesangial cells, which causes matrix accumulation due to stimulated TGF-b1 expressions and secretion. This could be a crucial link in the pathophysiology of developing diabetic nephropathy involving hyperglycemia and Ang II (Fig. 5.4).

7. Conclusion Angiotensin II plays a major role in maintaining renal homeostasis via acting on angiotensin receptors AT1 and AT2. Upstreaming of angiotensin II levels is implicated in dysregulation of oxidative and inflammatory status in renal vasculature. The evidence from the past literature implies that blocking of AT1 receptors may attenuate renovascular diseases such as hypertension, diabetes, atherosclerosis, and ischemic nephropathy.

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FIGURE 5.4 Diagrammatic representation of multiple effects of angiotensin II associated with distinct renovascular diseases leading to CKD/ESRD.

8. Conflict of interest There is no potential conflict of interest between the authors.

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antihypertensive drugs on renal outcomes: systematic review and meta-analysis. The Lancet 2005;366(9502):2026e33. Goldsmith DJ, Reidy J, Scoble J. Renal arterial intervention and angiotensin blockade in atherosclerotic nephropathy. Am J Kidney Dis 2000;36(4):837e43. Burke TA, Sturkenboom MC, Lu SE, Wentworth CE, Lin Y, Rhoads GG. Discontinuation of antihypertensive drugs among newly diagnosed hypertensive patients in UK general practice. J Hypertens 2006;24(6):1193e200. Taal MW, Thomson C. Renal association clinical practice guidelines for the treatment of patients with chronic kidney disease. 2007. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr JL, National High Blood Pressure Education Program Coordinating Committee. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 2003;289(19):2560e71. Renal Association. Standards Subcommittee. Treatment of adults and children with renal failure: standards and audit measures. Royal College of Physicians; 2002. van de Ven PJ, Beutler JJ, Kaatee R, Beek FJ, Willem PTM, Koomans HA. Angiotensin converting enzyme inhibitor-induced renal dysfunction in atherosclerotic renovascular disease. Kidney Int 1998;53(4):986e93. Colafella KMM, Bove´e DM, Danser AJ. The renin-angiotensin-aldosterone system and its therapeutic targets. Exp Eye Res 2019;186:107680. Ziegler T, Abdel Rahman F, Jurisch V, Kupatt C. Atherosclerosis and the capillary network; pathophysiology and potential therapeutic strategies. Cells 2020;9(1):50. Touyz RM, Anagnostopoulou A, Rios F, Montezano AC, Camargo LL. NOX5: molecular biology and pathophysiology. Exp Physiol 2019;104(5):605e16. Escudero P, Martinez de Maranon A, Collado A, Gonzalez-Navarro H, Hermenegildo C, Peiro C, Sanz MJ. Combined sub-optimal doses of rosuvastatin and bexarotene impair angiotensin II-induced arterial mononuclear cell adhesion through inhibition of Nox5 signaling pathways and increased RXR/PPARa and RXR/PPARg interactions. Antioxidants Redox Signal 2015;22(11):901e20. Piqueras L, Sanz MJ. Angiotensin II and leukocyte trafficking: new insights for an old vascular mediator. Role of redox-signaling pathways. Free Radic Biol Med 2020;157: 38e54. Durante A, Peretto G, Laricchia A, Ancona F, Spartera M, Mangieri A, Cianflone D. Role of the renin-angiotensin-aldosterone system in the pathogenesis of atherosclerosis. Curr Pharmaceut Des 2012;18(7):981e1004. Shu S, Zhang Y, Li W, Wang L, Wu Y, Yuan Z, Zhou J. The role of monocyte chemotactic protein-induced protein 1 (MCPIP1) in angiotensin II-induced macrophage apoptosis and vulnerable plaque formation. Biochem Biophys Res Commun 2019; 515(2):378e85. Ding Y, Chen J, Cui G, Wei Y, Lu C, Wang L, Diao H. Pathophysiological role of osteopontin and angiotensin II in atherosclerosis. Biochem Biophys Res Commun 2016;471(1):5e9. Lubrano V, Balzan S. Roles of LOX-1 in microvascular dysfunction. Microvasc Res 2016;105:132e40. Kattoor AJ, Kanuri SH, Mehta JL. Role of ox-LDL and LOX-1 in atherogenesis. Curr Med Chem 2019;26(9):1693e700. Jacobson HR. Ischemic renal disease: an overlooked clinical entity? Kidney Int 1988; 34(5):729e43.

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[113] Garcı´a-Donaire JA, Alca´zar JM. Ischemic nephropathy: detection and therapeutic intervention. Kidney Int 2005;68:S131e6. [114] Fatica RA, Port FK, Young EW. Incidence trends and mortality in end-stage renal disease attributed to renovascular disease in the United States. Am J Kidney Dis 2001; 37(6):1184e90. [115] Eirin A, Textor SC, Lerman LO. Emerging paradigms in chronic kidney ischemia. Hypertension 2018;72(5):1023e30. [116] Textor SC, Lerman L. Renovascular hypertension and ischemic nephropathy. Am J Hypertens 2010;23(11):1159e69. [117] Safian RD, Madder RD. Refining the approach to renal artery revascularization. JACC Cardiovasc Interv 2009;2(3):161e74. [118] Hanif MO, Bali A, Ramphul K. Acute Renal Tubular Necrosis. StatPearls Publishing; 2022. Bookshelf ID: NBK507815. [119] Safian RD, Textor SC. Renal-artery stenosis. N Engl J Med 2001;344(6):431e42. [120] Legrand M, Mik EG, Johannes T, Payen D, Ince C. Renal hypoxia and dysoxia after reperfusion of the ischemic kidney. Mol Med 2008;14(7):502e16. [121] Sharfuddin AA, Molitoris BA. Pathophysiology of ischemic acute kidney injury. Nat Rev Nephrol 2011;7(4):189e200. [122] Friedewald JJ, Rabb H. Inflammatory cells in ischemic acute renal failure. Kidney Int 2004;66(2):486e91. [123] Pagtalunan ME, Olson JL, Meyer TW. Contribution of angiotensin II to late renal injury after acute ischemia. J Am Soc Nephrol 2000;11(7):1278e86. [124] Wolak T, Kim H, Ren Y, Kim J, Vaziri ND, Nicholas SB. Osteopontin modulates angiotensin IIeinduced inflammation, oxidative stress, and fibrosis of the kidney. Kidney Int 2009;76(1):32e43. [125] Basile DP, Donohoe D, Roethe K, Osborn JL. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol Ren Physiol 2001;281(5):F887e99. [126] Durvasula RV, Petermann AT, Hiromura K, Blonski M, Pippin J, Mundel P, Shankland SJ. Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int 2004;65(1):30e9. [127] Gross JL, De Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care 2005; 28(1):164e76. [128] Sawicki PT, Kaiser S, Heinemann L, Frenzel H, Berger M. Prevalence of renal artery stenosis in diabetes mellitusdan autopsy study. J Intern Med 1991;229(6):489e92. [129] Postma CT, Klappe EM, Dekker HM, Thien T. The prevalence of renal artery stenosis among patients with diabetes mellitus. Eur J Intern Med 2012;23(7):639e42. [130] Chade AR, Krier JD, Rodriguez-Porcel M, Breen JF, McKusick MA, Lerman A, Lerman LO. Comparison of acute and chronic antioxidant interventions in experimental renovascular disease. Am J Physiol Ren Physiol 2004;286(6):F1079e86. [131] Cooper ME. Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Diabetologia 2001;44(11):1957e72. [132] Mezzano S, Droguett A, Burgos ME, Ardiles LG, Flores CA, Aros CA, Egido J. Renin-angiotensin system activation and interstitial inflammation in human diabetic nephropathy. Kidney Int 2003;64:S64e70.

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[133] Lo´pez-Novoa JM, Rodrı´guez-Pen˜a AB, Ortiz A, Martı´nez-Salgado C, Lopez Hernandez FJ. Etiopathology of chronic tubular, glomerular and renovascular nephropathies: clinical implications. J Transl Med 2011;9(1):1e26. [134] Navarro-Gonzalez JF, Mora-Fernandez C. The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol 2008;19(3):433e42. [135] Ruggenenti P, Cravedi P, Remuzzi G. The RAAS in the pathogenesis and treatment of diabetic nephropathy. Nat Rev Nephrol 2010;6(6):319e30. [136] Jennings DL, Kalus JS, Coleman CI, Manierski C, Yee J. Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy-a metaanalysis. Clin Diabetol 2007;8(6):219e28. [137] Onozato ML, Tojo A, Goto A, Fujita T, Wilcox CS. Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB. Kidney Int 2002; 61(1):186e94. [138] Rossing K, Jacobsen P, Pietraszek L, Parving HH. Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy: a randomized double-blind crossover trial. Diabetes Care 2003;26(8):2268e74. [139] Epstein M. Re-examining RAS-blocking treatment regimens for abrogating progression of chronic kidney disease. Nat Clin Pract Nephrol January 2009;5(1):12e3. [140] Sharma N, Malek V, Mulay SR, Gaikwad AB. Angiotensin II type 2 receptor and angiotensin-converting enzyme 2 mediate ischemic renal injury in diabetic and nondiabetic rats. Life Sci 2019;235:116796.

CHAPTER

The role of angiotensins in the pathophysiology of human pregnancy

6

Kirsty G. Pringle, Eugenie R. Lumbers, Saije K. Morosin, Sarah J. Delforce School of Biomedical Sciences & Pharmacy, College of Health, Medicine & Wellbeing, University of Newcastle, Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia

1. Introduction Human pregnancy lasts approximately 40 weeks. Fertilization occurs within the fallopian tube, and the cluster of cells known as the blastocyst embeds into the lining of the uterus, which differentiates and becomes known as the decidua. The leading Angiotensin. https://doi.org/10.1016/B978-0-323-99618-1.00029-5 Copyright © 2023 Elsevier Inc. All rights reserved.

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edge of the blastocyst forms the placenta, which invades the decidua and first third of the myometrium, altering the structure of the maternal spiral arteries and forming a “lake” of maternal blood that bathes the placental chorionic villi where exchange between maternal and fetal circulation occurs. The placenta is the life source of the fetus during pregnancy; it is a pregnancy-specific organ that provides the baby with nutrients and oxygen and removes waste products of metabolism. The fetal membranes form a sac that surrounds the baby and placenta during pregnancy; they consist of two closely associated membranes: amnion and chorion. The amnion, commonly referred to as the “amniotic sac,” is the innermost membrane of the conceptus; it contains the amniotic fluid in which the fetus is bathed and is nonvascular. The chorion is the outer layer of the fetal membranes and is highly vascularized. Pregnancy for mammals demands an enormous and ever-changing adjustment in maternal metabolism and fluid and electrolyte balance to provide an optimal environment for the growth of the fetus/fetuses. By the time a human fetus is born at about 40 weeks, it weighs approximately 3.5 kg, is over 70% water, and is surrounded by amniotic fluid. The continuous supply of oxygen, nutrients, and fluids by the mother to the fetus and the removal of waste products of fetal metabolism, including heat and both gaseous and nongaseous substances requires considerable effort by the placenta and maternal organs such as the lungs, gastrointestinal tract, skin, uterus, and kidneys. This increased work by the mother to maintain placental perfusion and to nurture the fetus, as well as preparing organs such as the breasts for postnatal nutrition, demands a compensatory increase in cardiovascular function. It has long been recognized that the circulating renineangiotensinealdosterone system (RAAS) plays a major role in these cardiovascular adjustments and in maternal fluid balance. What is not widely known is the role(s) of intrauterine tissue renine angiotensin systems (RASs) in placental growth and function and hence in fetal growth. Nor is it appreciated that the interactions between the intrauterine and maternal RASs underpin some of the most common and serious of adverse pregnancy outcomes, namely pregnancy hypertension, preeclampsia and HELLP (hemolysis, activated liver enzymes, and low platelet counts), fetal growth restriction (FGR) and gestational diabetes mellitus (GDM).

2. The renineangiotensin system There are two main functional arms of the RAS; both play a powerful role in modulating the actions of angiotensin (Ang) II. This is particularly the case in pregnancy. The two arms of the RAS are the angiotensin-converting enzyme (ACE)-Ang II-Ang II type 1 receptor (AT1R) axis (through which most of the well-known actions of the RAAS are mediated, see Fig. 6.1) and the more newly discovered Ang IIe angiotensin-converting enzyme 2 (ACE2)-Ang-(1e7)-MasR axis [1]. The Ang IIe ACE2eAng-(1e7)eMasR axis controls and counteracts, through various pathways, many of the effects of the Ang IIeAT1R axis.

2. The renineangiotensin system

FIGURE 6.1 The renin-angiotensin system (RAS) cascade. ACE, angiotensin-converting enzyme; AD, aspartate decarboxylase; AGT, angiotensinogen; ANG, angiotensin; APA, aminopeptidase A; APN, aminopeptidase N; AT1R, angiotensin II type 1 receptor; IRAP/ AT4R, insulin-regulated aminopeptidase/angiotensin II type 4 receptor; MasR, MAS1 oncogene receptor; MgrD, MAS related G proteinecoupled receptor D; MLDAD, mononuclear leukocyte-derived aspartate decarboxylase; NEP, neprilysin; (P)RR, (pro) renin receptor. Adapted from Chappell MC. Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute? Am J Physiol Heart Circ Physiol 2016;310(2):H137e52 and Hrenak J, Paulis L, Simko F. Angiotensin A/Alamandine/MrgD Axis: another clue to understanding cardiovascular pathophysiology. Int J Mol Sci 2016; 17(7) and created with BioRender.com.

Historically, the RAS has been regarded as a circulating endocrine system and its paracrine and autocrine functions have been largely ignored. This had led to a lack of insight into the role(s) of tissue RASs. There is, however, an important intrarenal RAS (iRAS) [3] as well as an intraocular RAS [4], an intraovarian RAS [5] and an intrauterine RAS [6]. In fact, local or tissue RASs are ubiquitous. Fig. 6.1 describes the RAS cascade. It should be noted that there are other receptors besides those mentioned before that are activated by various angiotensin peptides. We will predominantly address the interactions between the two main axes

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of the RAS, but it is important to appreciate that they are supplemented/affected by the actions of other peptidases. With respect to the circulating RAAS, renin, a serine protease, is responsible for the formation of circulating Ang II. Active renin is only secreted by the juxtaglomerular cells lining the renal afferent arterioles. It is released and regulated in such a way that it can maintain circulating blood volume and tissue perfusion. Active renin can be formed from prorenin by the removal of a 28-amino acid prosequence that covers its catalytic site. Prorenin is expressed not only in the kidney but also throughout the body in various organs and tissues. It can be activated spontaneously (about 1%), enzymatically by proteases such as cathepsin, trypsin, etc. [7], cold and low pH, and perhaps more significantly, by the extracellular portion of a membrane-bound vacuolar (v)ATPase, known as the (pro)renin receptor ((P)RR). [8]. The (P)RR not only activates prorenin but is also an accessory protein for a proton pump, the v-ATPase. The (P) RR also activates mitogen-activated protein kinase (MAPK) pathways independent of its role in the formation of Ang II and is involved in constituting the Wnt receptor complex [9]. Since prorenin is the only source of active renin in tissues, it follows that any role for active renin in tissue RASs requires activation of prorenin by one or more pathways. Renin cleaves a 10-amino acid peptide, Ang I, from a large 44 kDa serpin, angiotensinogen (AGT), which is produced predominantly in the liver, although it is also expressed in other tissues. Importantly, especially in terms of pregnancy, estrogens increase circulating levels of AGT [10]. Ang I has no biological activity; it is converted by ACE, a dipeptidyl-carboxypeptidase that interacts with a number of peptidergic pathways. ACE removes two amino acids from Ang I and produces the octapeptide, Ang II, the major biologically active peptide in the RAS (Fig. 6.1). The major actions of Ang II result from its interaction with a G proteinecoupled receptor (GPCR) namely the AT1R. Fig. 6.2 is a summary diagram of the actions of Ang peptides resulting from their interaction with several GPCRs and the enzyme, insulin-regulated aminopeptidase (IRAP/LNPEP/AT4R). Ang II is degraded to smaller peptides by several pathways (Fig. 6.1), the most significant of which is the ACE2 pathway because it is the major pathway for Ang II degradation and because its end product, Ang-(1e7), antagonizes many of the actions of Ang II. Ang-(1e7) can also be formed from other precursor Ang peptides by the combined actions of ACE, ACE2 (Fig. 6.1), and neprilysin (NEP) on Ang I. This latter pathway may be important for the intrarenal production of Ang(1e7) [12]. Recently, Nonn et al. [13] have described a significant role for the interactions between maternally produced Ang IV and the placental AT4R (IRAP/LNPEP), which decreases placental mitochondrial respiration and increases placental leptin. The (P)RR, ACE, and ACE2 are membrane bound; both ACE and ACE2 are ectoenzymes. ACE2 has a 40% homology with ACE. These three components of the RAS can be shed into the circulation so plasma levels may reflect their cellular expression and/or rate of shedding from cell membranes. High levels of soluble

2. The renineangiotensin system

FIGURE 6.2 Physiological actions produced by angiotensin (Ang) peptide activation of insulinregulated aminopeptidase/Ang II type 4 receptor (IRAP/AT4R), Ang II type 1 receptor (AT1R), Ang II type 2 receptor (AT2R), MAS-related G proteinecoupled receptor D (MgrD), and MAS1 oncogene receptor (MasR). BK, bradykinin; cGMP, cyclic guanosine monophosphate; NO, nitric oxide; NOS, nitric oxide synthase; ROS, reactive oxygen species; SNS, sympathetic nervous system. Adapted from Lumbers ER. Chapter 10: The physiological roles of the renin-angiotensin aldosterone system and vasopressin in human pregnancy. In: Kovacs CS, Deal CL, editors. Maternal-fetal and neonatal endocrinology: Academic Press; 2020:129e45 and created with BioRender.com.

ACE2 (sACE2) in the blood may, as in myocardial fibrosis, be associated with loss of ACE2 from the myocardium and a poor prognosis [14]. The (P)RR is also shed from cell membranes. There is a correlation between serum creatinine and s(P)RR levels suggesting that (P)RR is involved in the progression of chronic kidney disease (CKD) [15]. Soluble (P)RR increases the catalytic activity of circulating renin [16], and loss of s(P)RR reduces the hypertensive response to Ang II infusion and the adverse effects of Ang II infusions on renal function [17]. The effects of s(P)RR are induced by its direct interaction with the Ang IIeAT1R [18]. Interestingly, high levels of s(P)RR are associated with GDM, preeclampsia, and FGR as described in detail in the following. Although Fig. 6.1 shows a variety of actions of the RAS, its two major physiological roles are regulated through the direct actions of Ang peptides mediated by interaction with receptors (Fig. 6.2) and their indirect actions within the brain and on the sympathoadrenal systems. These direct and indirect actions of Ang peptides modulate cardiac output and vascular tone. The RAS regulates blood pressure and tissue perfusion. It also regulates aldosterone secretion and the activity of the iRAS and so influences blood volume. It should be noted that most of these actions

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are mediated via the AT1R. The interactions of Ang II on its AT2R and of its degradation product Ang-(1e7) on the MasR antagonize actions mediated by Ang IIeAT1R. In addition, Ang II via AT1R stimulates the production of reactive oxygen species (ROS) and promotes inflammation, proliferation, and fibrosis; actions that are also antagonized via Ang IIeAT2R and Ang-(1e7)eMasR interactions. The proliferative and proinflammatory effects of Ang IIeAT1R and their antagonism by AT2R and MasR are produced by tissue RASs. Since there is no secretion of active renin by tissues other than the kidney, prorenin must be activated by tissue proteases or the (P)RR. Alternatively, Ang II can be formed from AGT or Ang I by other tissue peptidases that can also form angiotensin peptides (Fig. 6.3). Therefore, in tissues, the production of Ang peptides is not confined exclusively to the major pathways of the circulating RAS nor is production necessarily produced in response to demand. The degree to which tissue Ang peptides are regulated so that

FIGURE 6.3 Alternate proteases and enzymes that affect generation of angiotensin II (Ang II). Prorenin can be cleaved by various proteases/peptidases into its active form. AGT can be cleaved by various enzymes to directly form Ang II. Chymase can cleave Ang I to form both Ang(1e12) and Ang-(1e25), both of which can be subsequently cleaved by chymase to form Ang II. AGT, angiotensinogen; Ang, angiotensin; t-PA, tissue plasminogen activator. Adapted from Belova LA. Angiotensin II-generating enzymes. Biochemistry (Mosc) 2000;65(12):1337e45 and Lumbers ER, Head R, Smith GR, et al. The interacting physiology of COVID-19 and the renin-angiotensinaldosterone system: key agents for treatment. Pharmacology Research & Perspectives. 2022;10(1):e00917, and created with BioRender.com.

3. The circulating renineangiotensinealdosterone system

their production is appropriate to demand is unknown. It does seem, however, that increased production of Ang II and hence activation of the AT1R is accompanied by an associated increase in the production of Ang-(1e7), which limits its activity. Thus, there is normally a balance between the opposing activities of the two arms of tissue RASs. Since the major pathway for degradation of Ang II is via the activity of the enzyme ACE2 (Fig. 6.1), increases in Ang-(1e7) levels in response to increased Ang II production could simply be the result of increased levels of Ang II driving the reaction. However, in some situations, such as postmyocardial infarction, myocardial ACE2 expression is increased [20]. Furthermore, Ang II-AT1R can downregulate ACE2 expression and upregulate ACE in human renal tubular cells [21]. When ACE2 is destroyed by SARS-CoV-2 [19], by ACE2 antibodies [22], or as a result of genetic manipulation, so that Ang II cannot be hydrolyzed, excess Ang II activates a number of pathways involved in inflammation and vasculopathy mainly by stimulating the production of ROS. Thus, ACE2 deficiency could play a role in placental insufficiency, FGR, and preeclampsia as discussed in the following.

3. The circulating renineangiotensinealdosterone system in normal pregnancy The maternal cardiovascular system increases its capacity through the growth of new blood vessels and relaxation of maternal vessels. Cardiac output increases, so although blood pressure falls in early gestation (first trimester), it normalizes in the second trimester. The increase in cardiac output and increased capacitance of the vascular system means that there must also be a concomitant expansion in maternal circulating plasma volume. The RAAS is the major endocrine system controlling salt, and therefore, water balance in response to homeostatic demand and through its many actions maintains tissue perfusion. So, it is not surprising that both circulating and tissue RASs are activated in pregnancy. The RAAS stimulates sodium reabsorption not only by the kidney but also across many exocrine glands such as the salivary glands, sweat glands, and intestinal mucosa. Fig. 6.4 shows the mechanisms via which the RAAS maintains blood pressure and therefore tissue perfusion.

3.1 Changes in components of the RAAS in human pregnancy The RAAS is activated before implantation occurs, i.e., during the luteal phase of the menstrual cycle, which occurs after ovulation [24]. Circulating renin, Ang II, and aldosterone levels are increased at this time. It is possible that luteal activation of the RAAS is related to the increase in progesterone levels, which antagonize the actions of aldosterone. However, in early pregnancy, the most spectacular rise is in

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FIGURE 6.4 Actions of the renineangiotensin system on maternal cardiovascular and renal physiology in pregnancy. Angiotensin (Ang) II acting via the Ang II type 1 receptor (AT1R) maintains maternal blood pressure and cardiac output in pregnancy via its actions in the brain, vasculature, and kidney. Ang II acting via the AT2R and Ang-(1e7) acting via its receptor, MasR, promotes uteroplacental perfusion by vasodilation. iRAS, intrarenal renineangiotensin system; SNS, sympathetic nervous system. Adapted from Lumbers ER, Pringle KG. Roles of the circulating renin-angiotensin-aldosterone system in human pregnancy. Am J Physiol Regul Integr Comp Physiol 2014;306(2):R91e101 and created with BioRender.com.

prorenin levels. The ovary is the source of this prorenin. Subsequently, and presumably in response to homeostatic demand, active renin levels rise [25]. Therefore, in early gestation, since prorenin is inactive, increased Ang II levels are due to increased secretion of AGT produced by the liver in response to high levels of estrogen secreted by the ovary. It is possible that these high levels of circulating AGT/Ang II also activate the iRAS, which could be important in maintaining renal sodium reabsorption in the face of the 50% increase in renal blood flow and glomerular filtration rate (GFR) that occurs in early pregnancy [23]. From about 12 weeks onward, it appears that the rise in AGT is not sufficient to sustain the increasing demand for Ang II and aldosterone, so the activity of the circulating RAAS is activated by increased release of active renin from the kidney. As the cardiovascular system increases its capacitance and blood pressure falls, renal

4. The intrarenal RAS in pregnancy

baroreceptors, arterial baroreceptors, and low-pressure baroreceptors are activated. This stimulates renin release by increased renal sympathetic nerve activity acting via b2-adrenergic receptors on the juxtaglomerular cells lining the afferent arteriole. Low-pressure (atrial) baroreceptors play a critical role in sensing demand [26] as they are sensitive to changes in central blood volume before there are changes in mean arterial pressure. Sodium deficiency in pregnancy is not only associated with marked increases in renin secretion but also acts as a very powerful direct stimulus to aldosterone secretion, an effect seen in Indigenous South American pregnant women who have a low salt intake [23], so that the rise in plasma aldosterone can be many times greater than the rise in renin levels. It is widely accepted that changes in renin and AGT control the activity of the circulating RAS, but little is known about placental/decidual expression, production, and secretion of Ang-converting enzymes (ACE and ACE2) and other enzymes also involved in their formation (e.g., NEP). Circulating levels of ACE and ACE2 are increased in pregnancy [27] and NEP can also be detected. Since ACE is usually localized to the fetal placental vascular endothelium [28], it is unlikely that it is the source of the increased maternal ACE levels although decidual ACE may well be. On the other hand, both NEP [29] and ACE2 are localized in the syncytiotrophoblast, and the increased levels seen in pregnancy could therefore be placental in origin. The significance of these observations remains to be clarified, but as ACE directs the formation of Ang II and ACE2 regulates Ang-(1e7) production, any changes in pathological pregnancies may alter the balance between the opposing actions of the two peptides [27,30] (see Fig. 6.1).

4. The intrarenal RAS in pregnancy In the kidney, all components of the RAS are present, and Ang II stimulates the production of proximal tubular AGT, collecting duct renin and AT1R receptors (Fig. 6.5). Circulating Ang II is internalized in proximal tubular cells by AT1Rdependent mechanisms. Thus, Ang II concentrations in proximal tubular cells and interstitial fluid are higher than circulating levels of Ang II [3]. It has been known for many years that intrarenal AT1R is essential for the induction of Ang IIdependent hypertension and cardiac hypertrophy [32], and it has been suggested that inhibitors of the RAS (e.g., ACE inhibitors [ACEIs] and angiotensin receptor blockers [ARBs]) lower blood pressure through their actions in inhibiting intrarenal Ang II production or activity [3]. The role of the iRAS in human pregnancy is unknown. In pregnancy, there is a 50% increase in GFR, which would lead to a corresponding increase in sodium excretion unless tubuloglomerular balance is altered (Fig. 6.6). Tubuloglomerular balance is the compensatory increase in tubular sodium reabsorption by the renal tubules (particularly the proximal tubules) so that the fraction of filtered sodium that is reabsorbed remains constant (Fig. 6.6). This means that even though an increase in

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FIGURE 6.5 The intrarenal renineangiotensin system (iRAS). Components of the RAS (angiotensin [Ang] II, Ang I, renin, prorenin, and angiotensinogen [AGT]) are filtered from the maternal blood into the Bowman’s capsule. Within the nephron, mainly in the proximal tubule and collecting duct, different RAS components can be synthesized (including Ang II type 1 receptor [AT1R] and angiotensin-converting enzyme [ACE]) or reabsorbed. Components of the RAS that are not reabsorbed are excreted in the urine (Ang II, renin, prorenin, and AGT). Adapted from Roman RJ, Fan F, Zhuo JL. Intrarenal renin-angiotensin system: locally synthesized or taken up via endocytosis? Hypertension (Dallas, Tex: 1979) 2016;67(5):831e33 and created with BioRender.com.

GFR is associated with a concomitant increase in tubular sodium reabsorption (i.e., the fraction reabsorbed remains constant), a greater amount is also excreted. Therefore, during pregnancy, in which there is an increased demand for sodium to maintain extracellular volume, it follows that to compensate for the increase in sodium excretion caused by the 50% increase in GFR, tubuloglomerular balance must be reset. Increased activity of the iRAS is probably the mechanism via which this occurs (Fig. 6.6). Activation of the iRAS could occur as a result of the increase in circulating Ang II levels that normally occurs in pregnancy, which stimulates the production of proximal tubular AGT. In addition, high levels of estrogen may stimulate intratubular AGT production and the contribution of circulating AGT, which is increased in pregnancy, may also add to the increased generation of Ang II in the proximal tubule [3]. Ang II acting via the luminal epithelial sodium channel (ENaC) transporter enhances proximal tubule sodium reabsorption. The generation of AGT/Ang II by the proximal tubular RAS has downstream consequences. It promotes the collecting duct

4. The intrarenal RAS in pregnancy

FIGURE 6.6 The intrarenal renineangiotensin system (iRAS) is upregulated during pregnancy. (A) A hypothetical example of the effects of the pregnancy-induced increase in glomerular filtration rate (GFR) on salt excretion (plasma Naþ ¼ 140 mmol/L). In a nonpregnant woman (A), 99.5% of filtered sodium (Naþ) is reabsorbed by the kidney and 0.5% is excreted. In a pregnant woman, the GFR is increased by 50% and, although 99.5% of filtered sodium is reabsorbed, the excretion of 0.5% would result in an increase in sodium excretion (about 50 mmol/day of extra sodium). Sodium is essential to maintain circulating blood volume. If the iRAS is activated in pregnancy by high angiotensin (Ang) II or angiotensinogen (AGT), then fractional sodium excretion will be reduced, and excess sodium is not excreted. (B) The iRAS is activated in normal pregnancy as indicated by the increase in the urinary angiotensinogen (AGT)/creatinine ratio; it continues to increase throughout pregnancy, compensates for the increased GFR, and helps maintain blood volume. (C) In women with pregnancy complications, there is a significant decrease in the urinary AGT/creatinine ratio, suggesting decreased iRAS activity, which may underlie the pathogenesis of hypertensive pregnancy pathologies. Different superscripts (a, b) denote significant differences between groups. Data in (B) and (C) adapted from Pringle KG, de Meaultsart CC, Sykes SD, et al. Urinary angiotensinogen excretion in Australian indigenous and non-indigenous pregnant women. Pregnancy Hypertens. 2018;12: 110e7 and figure partially created with BioRender.com.

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RAS to generate Ang II and enhances sodium reabsorption (Fig. 6.5). The collecting duct has two main cell types, principal cells, and intercalated cells. The former produce both renin and prorenin, the latter contain the (P)RR [34]. Proximal tubular AGT and possibly plasma-derived AGT are acted on within the tubular lumen by renin, which is secreted in response to Ang II, prostaglandins, arginine vasopressin (AVP), and bradykinin (BK). Ang II acts via AT1R and stimulates the luminal ENaC transport of sodium as does the (P)RR. Renin is released by protein kinase C (PKC) edependent activation of the cAMPeprotein kinase A (PKA)eCREB pathway. The (P)RR has another role in that it can nonproteolytically activate prorenin, exposing its catalytic site so that it can hydrolyze AGT. This complex RAS in the collecting duct and proximal tubule can therefore alter tubuloglomerular balance increasing tubular sodium reabsorption in response to increased production of circulating Ang II and AGT in pregnancy [34]. Urinary (u)AGT is a measure of the activity of the iRAS. If this is the case and the iRAS is activated in pregnancy to counterbalance the natriuretic effects of the increased GFR of pregnancy, then uAGT levels should be increased. This is, in fact the case. In pregnant women who have normal pregnancy outcomes, uAGT/creatinine is increased compared with non-pregnant women and levels increase as pregnancy progresses (Fig. 6.6B) [33]. Furthermore, active renin/creatinine levels are increased in the third trimester compared with the second trimester in non-Indigenous pregnant women who have normal pregnancy outcomes. When this compensatory response engineered by the iRAS is impaired, as in women with preeclampsia (when circulating Ang II levels are depressed) or when there is CKD outside of pregnancy [35], proximal tubular production of AGT is reduced and uAGT/creatinine levels are depressed. These changes have been reported in preeclampsia [36e38] and are impressively demonstrated in pregnancies with known adverse outcomes (such as GDM, and small for gestational age [33]). The lower activity of the iRAS, as indicated by uAGT/creatinine levels, may also indicate that renal function is impaired in Australian Indigenous pregnant women compared with non-Indigenous Australian women [33] possibly because there is subclinical renal dysfunction [35]. The activity of the iRAS therefore seems to be very sensitive to the integrity of the renal tubules. Thus, in patients with adverse pregnancy outcomes such as preeclampsia and diabetes or women with concurrent mild CKD, tubuloglomerular balance may not be adjusted so that more sodium is excreted leading to maternal volume contraction and reduced uteroplacental perfusion and contributing to reduced fetal growth.

5. The intrauterine renineangiotensin system: placenta, fetal membranes, and decidua 5.1 RAS components in the placenta in normal pregnancy

The placenta contains “tree-like” structures called chorionic villi; these are the site of nutrient and waste exchange, pictured in Fig. 6.7. The components of the RAS are

5. The intrauterine renineangiotensin system

FIGURE 6.7 Localization of renineangiotensin system (RAS) components in the intrauterine environment. RAS components in red text represent those that are present but not necessarily synthesized in the corresponding tissue/cell type. ACE, angiotensinconverting enzyme; ACE2, angiotensin-converting enzyme 2; AGT, angiotensinogen; (P) RR, (pro)renin receptor; Ang (1e7), angiotensin (1e7); Ang II, angiotensin II; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II type 2 receptor; AT4R, angiotensin II type 4 receptor (also known as IRAP [insulin-regulated aminopeptidase]); NEP, neprilysin; sACE, soluble ACE; sACE2, soluble ACE2; s(P)RR, soluble (P)RR; sNEP, soluble NEP. This figure was created with BioRender.com.

differentially expressed throughout the cells of the placental chorionic villi (Fig. 6.7). The syncytiotrophoblast is the major functional layer of the placenta, separating the maternal and fetal circulations. The syncytiotrophoblast contains all major RAS components except AT2R [27,28,39e43]. AT1R in the syncytiotrophoblast has only been detected at low levels [28,42] and recent studies by Nonn et al. suggest AT4R may be the dominant Ang peptide receptor in the syncytium [39]. Cytotrophoblast cells are the “stem cells” of the placenta because they either fuse and form the syncytiotrophoblast or differentiate into extravillous trophoblasts (EVTs). Cytotrophoblasts express prorenin, AT1R, (P)RR, ACE, ACE2, and NEP mRNA and protein [27,42,43]. Soluble forms of (P)RR, ACE, ACE2, and NEP are secreted by cytotrophoblasts, and levels of most of these components change when cytotrophoblasts form the syncytium [27,42,43]. EVTs are invasive cells of the placenta and contain all Ang II receptors (AT1R, AT2R, and AT4R) and although

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AT1R is the only receptor shown to be synthesized by EVTs, AT2R, and AT4R protein levels have been detected [28,41,42]. Similarly, (P)RR is synthesized by EVTs; and prorenin protein levels have been detected [28,44]. All of these RAS components are vital for the proliferation, invasion, and angiogenesis that is necessary for normal placentation [28,39,41,43]. Fetal fibroblast cells within the villous core are now thought to be the major site of expression of AT1Rs in the placenta [39]. However, fetal endothelial cells also express AT1R, where ACE and NEP proteins have also been detected [28,40,43]. AT1R, AGT, and ACE2 protein levels have been detected in fetal stromal cells [28]. Importantly, the MasR is not expressed in the placenta [28,39].

5.1.1 Effects of fetal sex, gestation, and labor on the expression of the placental RAS There is an overall decrease in the placental RAS expression across gestation [28]. Specifically, mRNA levels of prorenin, (P)RR, AGT, AT2R, and ACE2 are decreased in term placentae compared with early gestation placentae (6e16 weeks) [28,41]. On the other hand, both ACE mRNA expression and AT4R protein levels are increased in term placentae [28,41]. AT1R expression is unaffected by gestational age [41]. The increased expression of the RAS in early gestation placentae may indicate an essential role for the RAS in placentation, a time when proliferation, angiogenesis, and invasion are crucial [41]. At term, there seems to be a switch toward reliance on the AT4R arm of the RAS [39], an arm associated with maintaining cellular metabolism (Fig. 6.2) [13]. This demonstrates a potential placental RAS pathway switch during pregnancy, where the needs of the conceptus change from developing the placenta (by utilizing the PRR, AT1R, and AT2R pathways) to developing and maintaining the growing fetus (by utilizing both the AT1R and AT4R pathways, Figs. 6.1 and 6.2). Changes in the placental RAS with labor and fetal sex have also been examined. There is a decrease in placental (P)RR expression during labor, but labor does not affect the expression of placental prorenin, ACE, ACE2, AGT, AT1R, AT2R, or AT4R [6,39,44]. At term, fetal sex has no effect on the expression of RAS components in placentae from uncomplicated pregnancies [6].

5.2 RAS components in the intrauterine membranes in normal pregnancy Most RAS components are present in the fetal membranes. While prorenin and AGT proteins have been detected in the amnion and chorion, it is likely that these originate from the maternal decidua (see Section 5.3). (P)RR, ACE, ACE2, AT1R, and AT2R are synthesized in the fetal chorionic and amniotic membranes [6,44]. The presence of soluble forms of ACE, ACE2, and NEP in the fetal membranes has not yet been established.

5. The intrauterine renineangiotensin system

5.2.1 Effects of gestation and labor on the expression of the RAS in fetal membranes To date, gestational changes in expression of the RAS in the fetal membranes across gestation have not been established. However, we know that labor decreases ACE and increases AT2R mRNA levels in the fetal amnion but does not affect the expression of other RAS genes throughout the fetal membranes [6]. It is likely that since the AT2R pathway is generally anti-inflammatory, this could be a response to inflammation brought on by labor [6].

5.3 RAS components in the decidua in normal pregnancy The decidua is essentially the “pregnant endometrium” or the lining of the maternal uterine wall during pregnancy. The maternal decidua can synthesize almost all RAS components including prorenin, (P)RR, AGT, ACE, ACE2, AT1R, AT2R, MasR, and AT4R (albeit at low levels in healthy pregnancies) [6,44e46]. It is hypothesized that the decidua produces the AGT subsequently detected in both the chorion and amnion [39]. Alternatively, AGT could originate from the maternal blood and filter into the membranes and placenta. Interestingly, a similar phenomenon is believed to occur with amniotic prorenin; because although prorenin protein is detected in the amnion, amnion epithelial cells do not express prorenin mRNA [47]; and while chorionic cells can secrete prorenin [47], the decidua is thought to be the major source of chorionic renin [48]. Thus prorenin is thought to be secreted into the chorion, amnion, and neighboring amniotic fluid [49] by the underlying decidua [48,49]. While ACE has been detected across all membranes, it is predominately expressed by the maternal decidua where Ang II has also been detected [50]. Therefore, it is likely that Ang I is catalyzed in the decidua and secreted into the adjacent, ACEdeficient, chorionic and amniotic tissues [51]. Ang-(1e7) has also been detected in the maternal decidua at low concentrations where it is colocalized with its receptor, MasR [46].

5.3.1 Effects of fetal sex, gestation, and labor on the expression of the RAS in fetal membranes The decidual RAS is influenced by fetal sex. The decidua in women carrying a female fetus expresses and secretes more prorenin than decidua from women carrying male fetuses; this may mean that increased prorenin levels occur in chorion, amnion, and amniotic fluid if the fetus is female [46]. Furthermore, decidua from women carrying female fetuses also has increased expression of other RAS components including AGT, ACE, (P)RR, and MasR [46]. Thus, the decidual RAS is regulated in a sex-specific manner. Amnion (P)RR levels are strongly correlated to levels of expression of TGF-b1 [53]. Since overexpression of (P)RR has been shown to cause renal fibrosis through upregulation of TGF-b1, we postulated that this pathway could subsequently play a role in maintenance of the integrity of the fetal

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membranes; it could also explain why female babies are at less risk of preterm premature rupture of membranes (PPROMs) than male babies [52]. Gestational changes in the decidual RAS have not yet been determined. However, levels of both prorenin and (P)RR in the decidua decrease with labor onset, similar to what occurs in the placenta [44].

6. The RAS and hypertension in pregnancy Hypertension is a clinical sign not a disease entity. Although it can be a sign of underlying disease (so-called secondary hypertension), there is no known cause for most cases of hypertension (so-called essential hypertension). Secondary hypertension is associated with underlying pathologies such as CKD or endocrine dysfunction. Interestingly, primary hyperaldosteronism is being increasingly recognized as an underlying cause of essential hypertension [53]. In pregnancy, the increased compliance of the maternal cardiovascular system means that blood pressure is usually below non-pregnant levels in gestation and only returns to non-pregnant levels in mid-gestation. Pregnancy-associated hypertension does occur, however, and it can be classified as follows: (1) chronic hypertension (existing prior to pregnancy), (2) gestational hypertension, which is hypertension (>140/90 mmHg) occurring after about 20 weeks’ gestation (term ¼ 40 weeks) in an otherwise normotensive woman, and (3) preeclampsia, which also occurs at about 20 weeks’ gestation. Preeclampsia is the second most common cause of maternal mortality, and it is characterized by hypertension and maternal organ damage, usually signaled by proteinuria. Preeclampsia can be classified as “early” (occurring between 20 and 34 weeks of gestation) and “late” preeclampsia (occurring >34 weeks of gestation). Early-onset preeclampsia is likely to be a more severe clinical entity and is related to poor or shallow placentation. Late preeclampsia often occurs secondary to chronic renal disease/preexisting chronic hypertension. HELLP syndrome (hemolysis, activated liver enzymes, and low platelet count) occurs in about 10%e20% cases of severe preeclampsia [54]. Both preeclampsia and HELLP are serious diseases requiring immediate intervention. They can only be cured by delivery of the baby and removal of the placenta [55]. Preeclampsia can occur as an isolated clinical entity or in pregnant women with preexisting hypertension, chronic renal disease, or obesity [56]. As stated before, early-onset preeclampsia is thought to occur because there is poor trophoblast invasion of the maternal decidua and insufficient remodeling of the maternal spiral arteries. The spiral arteries open into the intervillous space of the placenta supplying the placenta and fetus with nutrients and oxygen. Failure to remodel the maternal spiral arteries results in placental ischemia, which generates ROS that damage the placenta (Fig. 6.8) [57]. Therefore, it is not surprising that preeclampsia can be induced in animal models by reducing uterine perfusion pressure (RUPP model) [58]. Overexpression of the placental RAS is also a cause of

6. The RAS and hypertension in pregnancy

FIGURE 6.8 The role of the uteroplacental and intrarenal renineangiotensin systems (RASs) in the pathogenesis of preeclampsia. (A) The role of the uteroplacental RAS in preeclampsia, a pathology defined by placental ischemia/reperfusion. Placental ischemia/reperfusion leads to increased production of reactive oxygen species (ROS) and inflammatory/ immune cells, which in turn increases the activity of the placental and decidual RAS. This culminates in increased soluble (pro)renin receptor (s(P)RR), angiotensin II (Ang II), and angiotensin II type 1 receptor autoantibody (AT1-AA) levels, all of which act on the Ang II type 1 receptor (AT1R) to increase various antiangiogenic factors including soluble fmslike tyrosine kinase 1 (sFLT), soluble endoglin (sEng), endothelin 1 (ET-1), and endothelin A receptor autoantibodies (ETAR-AAs), all of which contribute to the pathogenesis of preeclampsia. (B) The role of the intrarenal RAS (iRAS) in preeclampsia. In preeclamptic pregnancies, there are increased AT1R autoantibodies that cannot be filtered by the kidney. This leads to a decrease in circulating Ang II levels and a consequent decrease in iRAS activity, which ultimately leads to reduced blood volume and uteroplacental perfusion. This figure was created with BioRender.com.

preeclampsia in animal models. Preeclampsia occurs if a female rodent transgenic for human AGT (hAGT) is mated with a male rodent transgenic for human renin (hREN) [59,60]. In early gestation and in women who later developed gestational hypertension or preeclampsia, there were sexually dimorphic changes in blood pressure, uterine perfusion pressure, and Ang peptide levels suggestive of early overactivity of the RAS and maternal cardiovascular changes (such as raised blood pressure

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and increased cardiac workload) [61]. A SNP in the ACE gene (A11860G) is associated with higher circulating ACE levels [62]. Furthermore, a SNP in the AGT gene, which leads to overexpression of AGT, predisposes to preeclampsia [63]. So, excess Ang II could be responsible for inadequate invasion of placental trophoblast through activation of nicotinamide adenine dinucleotide phosphate (NADPH) and generation of ROS [64]. Not only are levels of Ang II and the density of AT1Rs increased in preeclamptic placenta [65], but prorenin and (P)RR are also increased [66]. Furthermore, the novel endocytic receptor megalin, which can take up prorenin and endocytose maternal AGT, is increased in preeclamptic placenta [66]. The (P)RR is a vATPase and promotes megalin recycling by endosomal acidification. Thus, megalin-mediated transport is reduced by drugs that block the proton pump, vATPase, which is the (P)RR. Proton pump inhibitors (PPIs) inhibit the release of sFLT from preeclamptic placentae [67]. Since Ang II stimulates sFLT release, it would seem that increased activity of the RAS is generated by the interaction between placental prorenin and maternal AGT [66] and depends on placental prorenin and uptake of maternal AGT. The increase in placental prorenin and its receptor would activate the placental RAS, and the increased production of Ang II would not only generate ROS damage but also together, stimulate expression of sFLT-1 and other angiogenic factors, as well as generate autoantibodies to the AT1R as described in the following. The role of maternal AGT in placental synthesis of Ang II explains why maternal h AGT transgenic mice become hypertensive when mated with h renin male transgenic mice, but this does not occur when female h renin are mated with male h AGT transgenic mice [59,60]. Thus, it is the interactions between the maternal and placental/fetal RASs that cause preeclampsia. The placental damage induced by Ang II-stimulated production of ROS and ischemia reperfusion plus potential antigenicity of foreign (fetal) tissue stimulates production of AT1R autoantibodies (AT1-AAs) [68]. AT1-AAs bind to a 7-amino acid sequence in the second extracellular loop of the AT1R. They produce the same effects as Ang II binding to the AT1R, but AT1-AAs have a more sustained duration of action than Ang II [68]. The ontogenesis of AT1-AAs is obscure although the cytokine IL-17 appears to be involved. AT1-AAs are IgGs and are produced by B cells as their levels are reduced in B celledepleted animals [69]. It is perhaps not surprising that the major site of production of AT1-AAs is the decidua adjacent to the placenta [70]. Not only do AT1-AAs, like Ang II, stimulate the production of the antiangiogenic molecules, sFLT1, and soluble endoglin (sEng) [70], they also stimulate of production of endothelin-1 (ET-1), which contributes to the vasculitis of preeclampsia and HELLP [71]. About 80% of women with preeclampsia have detectable AT1-AAs, but they are not exclusive to pregnancy as they have been found in acute and chronic tissue rejection [72], malignant refractory hypertension [73], systemic sclerosis [74], and ovarian cancer [75]. AT1-AAs often occur in association with agonistic endothelin A receptor autoantibodies (ETAR-AAs). Very recently, both have been detected in patients with

6. The RAS and hypertension in pregnancy

COVID-19 where their presence is correlated with more serious disease [76]. Both ETAR-AAs and AT1-AAs are agonistic autoantibodies that do not interact with their alternate receptors, ETBR and AT2R (which antagonize those actions of ETA and Ang II mediated via the ETAR and AT1R, respectively) [76]. Since AT1-AAs do not activate the AT2R and have a longer duration of action than the natural ligand, it follows that they are much more effective than Ang II in effecting actions of Ang II mediated via the AT1R. Buttrup et al. showed that AT1-AAs were elevated in 100% of patients with severe preeclampsia or HELLP, and ETAR-AAs were elevated in 44% of cases. High levels of IL-17, which are also increased in autoimmune conditions, were associated with elevation of AT1-AAs and ETAR-AAs [77]. Interestingly, women who subsequently developed either gestational hypertension or preeclampsia and who were carrying male fetuses had higher levels of C-reactive protein at 15 weeks of gestation compared with women who had normal pregnancy outcomes [61]. This suggests an early involvement of inflammation in these women, which may underly the pathogenesis of hypertension. In animal models of preeclampsia in which RUPP is used to induce maternal hypertension or in hAGT transgenic female rodents mated with hREN transgenic males [71] AT1-AAs are elevated. Furthermore, infusions of purified immunoglobulins from pregnant humans suffering from preeclampsia cause a preeclamptic-like syndrome in pregnant rodents [78]. The presence of placentally produced Ang II and AT1-AAs explains all the clinical signs of preeclampsia. These include the placental actions of Ang peptides, in particular increased production of sFLT-1 and sEng as well as suppression of the renal (maternal RAS). The circulating RAS is, as explained before, exquisitely regulated to maintain fluid and electrolyte homeostasis, blood volume, and blood pressure (see Fig. 6.4). Since placentally produced non-regulated Ang II and AT1AAs cause sustained production of aldosterone and (together with sEng, sFLT, and ET-1) cause sustained vasoconstriction, renin secretion from the kidney into the circulation is suppressed and the regulated production of Ang II by the circulating RAS is reduced compared with levels seen in normotensive pregnant women [79,80]. Interestingly, ACE, sACE2, and sNEP enzymes are reduced in women with preeclampsia [27]. The significance of these observations in the pathogenesis of preeclampsia remains to be elucidated. Ang II present in maternal circulation may in fact be placental in origin [57]. AT1-AAs are not detected in routine assays of Ang peptides, yet all the symptoms of excess Ang II are present including increased vascular reactivity to Ang II, perhaps because excess Ang II-AT1R activity destroys vasodilator AT2Rs (particularly those in the uteroplacental circulation [81]) leading to increased uterine artery resistance seen at 20 weeks of gestation in pregnancies in which the fetus was female [61]. Lack of circulating Ang II as a result of suppression of renal renin release would result in lack of activation of the iRAS which, as described before, is postulated to increase tubuloglomerular balance to counteract the effects of the

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pregnancy-induced increase in maternal GFR and consequent salt loss. AT1-AAs are unlikely to be subjected to glomerular ultrafiltration because they are large molecules (150 kDa); the glomerular barrier to ultrafiltration is approximately 70 kDa [82]. Thus, in severe preeclampsia, failure of activation of the iRAS, as evidenced by lower than normal uAGT/creatinine [33], would lead to a reduction in circulating blood volume, further threatening uteroplacental perfusion and exacerbating the effects of placental hypoxia.

7. The role of the RAS in regulating fetal growth Fetal growth restriction (FGR) is defined as the failure of the fetus to achieve its full growth potential in utero and affects approximately 5% of all live births [83]. The origins of FGR are multifactorial. About a third of cases are attributed to either fetal (e.g., aneuploidy) or placental (e.g., infarcts) defects [83]. The remaining two-thirds of cases are of unknown etiology and are categorized as “idiopathic FGR.” A specific diagnosis is frequently difficult as FGR is often complicated or occurs in association with other pregnancy complications, such as GDM or preeclampsia. Despite this, it is generally accepted that placental insufficiency, arising as a consequence of inadequate trophoblast invasion into the decidua and maternal spiral arterioles (see before), is an important contributor to the development of FGR [84]. In support of this theory, there is significant evidence that FGR-affected placentae have significantly smaller weights, volumes and diameters [85]. Abnormal placental shape (including extrachorial and bilobate placenta) is also associated with poor placental growth and FGR [86]. Moreover, as in preeclampsia, FGR pregnancies are often associated with gestational hypertension. Indeed, in 55% of FGR biopsy samples, there was noticeable absence of the physiological transformation of the spiral arteries in the myometrial segment of the uterus [87]. This has subsequently been associated with greater pulsatility of maternal blood flow, indicative of poor placental perfusion, in women who delivered a small for gestational age (SGA) baby [88]. While the specific functional consequences of the circulating and uteroplacental RAS on the pathogenesis of FGR have not yet been fully elucidated, the similarities between the FGR and preeclamptic phenotype suggest a possible role for the RAS in its pathogenesis.

7.1 Changes in the maternal circulating RAAS in pregnancies associated with FGR There has been no comprehensive examination of circulating RAAS components in pregnancies complicated by FGR although a few studies have looked at some of the individual components in isolation. With regard to circulating aldosterone and renin, data from these studies are somewhat conflicting. An early study by Salas et al. found that pregnancies with growth restricted fetuses had lower serum aldosterone but similar plasma renin activity (PRA) compared with uncomplicated pregnancies

7. The role of the RAS in regulating fetal growth

[89]. A later study, however, reported that FGR pregnancies have normal maternal PRA and aldosterone levels [90]. To the best of our knowledge, there have been no studies examining the maternal levels of AGT in pregnancies associated with FGR. Recently, Tamanna et al. examined the levels and activity of circulating RAS enzymes in pregnancies associated with SGA babies [91]. In SGA pregnancies, ACE and ACE2 levels were higher in early-mid pregnancy compared with normal pregnant women [91], suggesting that an imbalance in the RAS enzymes that favors the Ang II-AT1R pathway may be involved in the pathogenesis of SGA and potentially FGR (Fig. 6.9). Given the recent interest in s(P)RR levels in women with preeclampsia, it is perhaps not surprising that interest in this circulating factor is growing and that investigations into its potential role as a biomarker for FGR are emerging. Studies

FIGURE 6.9 The postulated role of the renineangiotensin system (RAS) in the pathogenesis of fetal growth restriction (FGR). The placental angiotensin II type 1 receptor (AT1R) is overactivated by the elevated levels of AT1R autoantibodies (AT1-AAs), high levels of s(P) RR and an increase in the angiotensin-converting enzyme (ACE)/ACE2 ratio that favors the production of Ang II. Excess AT1R activation in the placenta is likely to reduce uteroplacental perfusion and inhibit amino acid transport, resulting in decreased oxygen and nutrient transport across the placenta and, ultimately, cause FGR.

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have demonstrated that maternal serum s(P)RR levels are significantly higher in patients with FGR [92,93] and are positively correlated with serum prorenin levels [92]. Soluble (P)RR concentrations are negatively correlated with birth weight and placental weight [93]. One study has also shown that high s(P)RR concentrations in cord blood are associated with an increased likelihood of an SGA birth [94]. The mechanism by which s(P)RR in the maternal and fetal circulations may be impacting on fetal growth is unknown but it could be due to the known agonistic actions of s(P)RR on the AT1R [18] (Fig. 6.9).

7.2 Changes in placental RAS expression in pregnancies associated with FGR Surprisingly, there have been very few studies examining the expression of placental RAS components in pregnancies associated with FGR. A recent study by Delforce et al. found that the mRNA expression of AT1R, ACE2, and NEP was significantly reduced in FGR placentae compared with controls [30]. Similarly, the mRNA and protein levels of AT1R as well as AT1R ligand binding have been shown to be significantly reduced in FGR pregnancies [43,95e97]. The reduced expression of ACE2 and/or NEP could limit the production of Ang-(1e7), which is a vasodilator, and result in elevated placental Ang II levels, which is a vasoconstrictor. This dysregulation of the placental RAS could ultimately lead to reduced placental perfusion that is evident in FGR (Fig. 6.9). The reduction in AT1R expression thus likely reflects activation of the placental Ang II/AT1R pathway and subsequent receptor downregulation. Similar decreases in placental ACE2 expression can be found in various animal models of FGR. For example, FGR caused by maternal protein restriction in rats is associated with reduced placental ACE2 expression [98]. Dexamethasone administration causes a reduction in fetal weight and labyrinthine zone weight accompanied by a decrease in placental ACE2 mRNA and protein levels and a decrease in Ang(1e7) levels in the placenta [99]. Furthermore, ACE2 knockout mice have reduced fetal weights, reduced fetal lengths, and a reduction in the fetal-to-placental weight ratio, an indirect measure of placental insufficiency [100,101]. They have also been shown to have reduced plasma Ang-(1e7) levels and increased placental Ang II levels [101]. Together, these studies suggest that ACE2 deficiency and associated elevated placental Ang II levels may contribute to FGR (Fig. 6.9). Indeed, studies have shown that Ang II decreases system A amino acid transport activity of term villous placenta through AT1R activation [102] and suggest that overactivation of the uteroplacental RAS affects fetal growth in part by limiting amino acid transport (Fig. 6.9). Another possible source of excess AT1R activation in FGR pregnancies may be agonistic AT1R-AAs. These antibodies have also been shown to track with abnormal second trimester uterine artery Doppler waveform [103]. These autoantibodies occur in cases of reduced uteroplacental perfusion, many of whom subsequently develop FGR (with or without preeclampsia). Using an AT1R-AA-induced animal model of

8. The RAS in gestational diabetes

preeclampsia, Irani et al. showed that AT1R-AAs induce placental apoptosis, cross the mouse placenta, enter the fetal circulation, and lead to small fetuses with organ growth restriction [104]. Furthermore, AT1R-AA-induced FGR and placental apoptosis were diminished by either losartan or an autoantibody-neutralizing peptide [104]. AT1-AAs have also been shown to inhibit spiral artery remodeling in normal pregnant rats [105]. Together, these studies suggest that AT1R-AAs can adversely impact fetal growth, both by crossing the placenta and acting directly on the fetus, and by inducing placental damage (Fig. 6.9).

8. The RAS in gestational diabetes Diabetes affects approximately 10%e12% of pregnancies worldwide [106,107]. About 9% of women develop GDM, and 1% have preexisting (type 1 or type 2) diabetes mellitus (DM). The prevalence of diabetes in pregnancy has risen steadily over the past few decades, coinciding with the ongoing epidemic of obesity and type 2 diabetes. Although GDM generally resolves after pregnancy, women with GDM have higher rates of caesarean section, induced labor, preexisting and gestational hypertension, preeclampsia, and polyhydramnios [108,109]. In addition, babies of mothers with GDM have higher rates of preterm birth, stillbirth, low and high birthweight, birth trauma, neonatal hypoglycemia, and respiratory distress syndrome. They also have an increased predisposition to type 2 DM (T2DM) later in life. The mechanisms of GDM are poorly characterized; however, GDM is now considered one of the “great obstetrical syndromes” recognizing the contribution of the placenta in its pathology. Hyperglycemia, such as that seen in women with GDM, affects placental development and function [110]. The placenta, which separates the maternal and fetal circulations, is sensitive to a hyperglycemic milieu. Alterations in placental development and subsequent vascular dysfunction are present in over 85% of pregnant women with diabetes [110]. Various abnormalities in placental structure have been reported in GDM pregnancies, including greater placental weight and thickness [109,110], increased branching and non-branching angiogenesis [111], thickening of the trophoblast basement membrane [112], increased oxidative stress [113] and tissue injury, including calcium and fibrin deposits, infarction, and fibrosis [114]. It is these placental morphologies that alter transplacental transport and alter fetal growth in women with GDM. Given these changes in placental structure and function as well as the known role of the RAS in the pathogenesis of diabetes outside of pregnancy, it is postulated that the circulating and intrauterine RASs are likely to play an important role in diabetes that occurs in pregnancy. A hallmark feature of insulin resistance and T2DM that occurs outside of pregnancy is increased activation of the RAAS. The RAS has also been strongly implicated in the pathophysiology of diabetes, on the basis of the therapeutic ability of ACEIs and ARBs to reduce the incidence of new-onset diabetes, improve insulin sensitivity, and decrease vascular complications in patients

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with diabetes [115]. From animal models, it is known that the application of ARBs improves glucose tolerance through enhancement of insulin-mediated glucose uptake in peripheral organs such as skeletal muscle, possibly due to changes in blood flow [116]. Despite this, the activity and role of the RAS in GDM has not been well characterized. With regard to the circulating RAAS in women with GDM, Chen et al. showed, in a cohort of 689 Chinese pregnant women, that plasma aldosterone levels were significantly higher in pregnant women with GDM compared with those with normal glucose tolerance (NGT) in pregnancy [117]. Plasma aldosterone and the aldosterone/PRA ratio were positively correlated with fasting blood glucose levels. This confirms an earlier small study also showing elevated aldosterone in diabetic pregnant women [118]. To the best of our knowledge, there have been no studies examining maternal levels of AGT in women with GDM and data on the levels of circulating prorenin and renin in women with GDM are conflicting. Sugulle et al. found no significant differences in maternal circulating prorenin or renin levels between GDM and pregnant women with NGT [119]. Similarly, Chen et al. reported no difference in PRA, although PRA was negatively correlated with fasting blood glucose [117]. Conversely, a subsequent study reported that circulating prorenin levels are elevated in women with GDM compared with women with NGT [120]. Reports on levels of s(P)RR in women with GDM are much more convincing. Numerous independent studies have demonstrated that s(P)RR levels in women with GDM are significantly higher compared with women with NGT [119,121e123]. Furthermore, s(P)RR concentrations in women with GDM are elevated early in pregnancy and may be a marker for predicting GDM [122,123]. Watanabe et al., in a prospective cohort study, found that women in the highest s(P)RR concentration quartile (Q4) were 2.90-fold more likely to develop GDM than women in the lowest quartile (Q1) [122]. It is well established that the (P) RR is upregulated in response to hyperglycemia [124] and contributes to pathological responses associated with DM [124,125]; however, its role in GDM is poorly characterized and much more research in this area is required. With regard to circulating Ang peptide levels, women with GDM have been shown to have a significant increase in Ang I levels when compared with NGT women. Furthermore, Ang-(1e7) levels are significantly reduced, but Ang II levels are unaltered when compared with NGT women [126]. This suggests that there may be an imbalance in the Ang peptides in women with GDM. Recent studies also suggest that there is an imbalance in the Ang receptors that favors the Ang IIeAT1R pathway. Serum P-LAP (AT4R) levels are reduced among patients with GDM [127]. Furthermore, in a streptozotocin-induced rodent model of GDM, Ang II induced vasoconstriction and increased AT1R but not AT2R expression in the aorta of GDM animals, reversing the characteristic blunted response to this peptide during pregnancy [128]. By shifting the balance between the RAS pathways toward the Ang IIeAT1R pathway, the RAS is likely to be responsible for the increased risk of hypertensive complications in women with GDM in pregnancy. However, more

References

comprehensive studies are required that consider the levels and activity of the angiotensin-converting enzymes as well as the angiotensin peptides and receptors. Future studies should also consider the impact of pharmacological and dietary management of diabetes in pregnancy on RAS components. To date, there are no published data on the intrauterine RAS in pregnancies with GDM.

9. Conclusions Both the circulating RAAS and iRAS play essential roles in regulating cardiovascular function and fluid and electrolyte homeostasis in pregnancy. However, if these RASs are not activated sufficiently or are overactivated, pregnancy complications may ensue. In addition, these various RASs may interact, and if, for example, the intrauterine RAS is dysfunctional as in preeclampsia, this can alter the activity of the circulating and intrarenal RASs, adversely affecting maternal cardiovascular and renal function, and enhancing the susceptibility of the mother to pregnancy complications. In pregnancies complicated by placental insufficiency, dysregulated placental RAS can alter the balance between the Ang II-AT1R and Ang-(1e7)-MasR pathways both locally and in the maternal circulation. This results in excess activation of the AT1R, failure of the circulating and intrarenal RAAS to respond to homeostatic demand, and impaired uteroplacental nutrient and oxygen transport, often culminating in the development of FGR, hypertension, or preeclampsia. With regard to GDM, we still have much to learn about the role of the RASs in this pathology. However, early evidence suggests that the circulating RAS, as in nonpregnant diabetics, is elevated in women with GDM. Many circulating RAS components could possibly be used as early predictors of GDM; however, their role in its pathology and potential alterations in the intrauterine RAS needs further research.

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CHAPTER

Hematopoietic bone marrow renin-angiotensin system in health and disease

7

Umit Yavuz Malkan, Ibrahim C. Haznedaroglu Department of Hematology, Hacettepe University School of Medicine, Ankara, Turkey

1. Introduction The renineangiotensin system (RAS) had initially been described as a circulating endocrine system. However, the paracrine and autocrine functions of organ- and tissue-based local RAS are further defined [1e3]. The leading active peptide of the RAS is angiotensin II (Ang II), which controls cellular growth in different tissues [4e6]. A locally active intracrine RAS in the bone marrow, which controls the growth, production, proliferation and differentiation of hematopoietic cells, has been defined by our research group [7]. After an intense literature debate, other studies confirm the existence of this local RAS in bone marrow. Ang II interacts with Ang II type 1 (AT1) receptor, which eventually leads to an increase in erythroid differentiation. This promoting activity of Ang II on erythropoiesis was totally eliminated by a specific AT1 receptor antagonist, losartan [8,9]. Human CD34þ hematopoietic stem cells have AT1a receptors. Losartan blocks the activity of Ang II on hematopoietic progenitor cells. Angiotensin-converting enzyme (ACE) plays a role in transformation of primitive stem cells into S-phase in hematopoietic bone marrow by decreasing tetrapeptide AcSDKP [10,11]. Circulating hematopoietic progenitors are altered by ACE inhibitors [12]. ACE is expressed by hematopoietic progenitors in the developing mouse embryo. Moreover, ACE and the other elements of RASdnamely, angiotensinogen, renin, and AT1 and angiotensin II type 2 (AT2) receptorsdare present in the paraaortic splanchnopleura (P-Sp) and in its derivative, the aorta-gonad-mesonephros region, in both human and mouse embryos [13]. In vitro perturbation of the RAS by administration of a specific AT1 receptor antagonist has shown to inhibit nearly completely the generation of blood CD45-positive cells from dissected P-Sp, implying that angiotensin II signaling is essential for the emergence of hematopoietic cells. The role of local RAS throughout embryogenesis, proposing that angiotensin II, via stimulation of AT1 receptor, increases the emergence of undifferentiated hematopoietic progenitors is evident.

Angiotensin. https://doi.org/10.1016/B978-0-323-99618-1.00007-6 Copyright © 2023 Elsevier Inc. All rights reserved.

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In inflammatory clinical conditions, including granuloma, atherosclerosis, chronic kidney disease, and bacterial infection, ACE expression increases in immune cells, particularly in myeloid cells [14,15]. Those evidence linking ACE functions to the pathogenesis of these acquired diseases favor that ACE has a vital role in immune functions. Furthermore, studies with mouse models of bacterial infection and tumor propose that ACE has a significant role in the immune responses of myeloid cells [16]. Blocking of ACE decreases neutrophil immune reaction to bacterial infection [17]. Moreover, ACE overexpression in myeloid cells increased bacterial and tumor resistance in mice [18]. The issues of how ACE stimulates myeloid cells and which ACE peptides control these effects are very important to understand human RAS. RAS has also a role in neoplastic hematopoiesis. Renin has been found in leukemic blast cells [19,20]. Higher bone marrow ACE levels in acute leukemic cases indicate that more ACE is secreted at leukemic bone marrow [20]. The local organ RAS systems as well as hematopoietic RAS are well described in the literature. The local bone marrow RAS stated as a potential treatment target in neoplastic hematological diseases [21]. The caudal-related homeobox gene 2 (CDX2) encodes an important transcription factor involved in tissue expansion and patterning of the posterior embryo, and it is shown to participate in ACE regulation in blood development and leukemia cells [22e24]. Although absent in normal bone marrowederived hematopoietic stem cells, CDX2 abnormally presented in acute myeloid leukemia cells, at levels that associate with the increase of ACE expression. These data underline the deleterious effect exerted by CDX2 upon abnormal reexpression in leukemia through the proliferative effect exerted by Ang II on hematopoietic cell growth [13,25]. Blood mononuclear cells are being analyzed as immunologic and pathologic responders to the new pandemic SARS-CoV-2 virus (CoV19). Blood mononuclear cells and myeloid cells that take up residence in various organs can harbor viral genomes for many years in lymphatic tissues, skin, and brain and act as a source for reinfection and/or postviral organ pathology [26]. Myeloid migratory cells are suspected to carry CoV19 to heart and brain with consequent late postviral immune pathologies [26]. The relationship between SARS-CoV19 and RAS is an important issue. An increase in polyclonal plasma cells, CD14þ CD64þ CD68þ active monocytes in bone marrow, and SARS-CoV-2 in the bone marrow by PCR analysis was demonstrated, indicating the presence of SARS-CoV-2 in the bone marrow [27]. The aim of this chapter is to focus on the impacts of the local bone marrow RAS on definitive and neoplastic hematopoiesis, as well as its interrelationships among atherosclerosis, hypertension, and COVID-19 syndrome (Fig. 7.1).

2. Local bone marrow renineangiotensin system in hematopoiesis

Hematopoiesis

Atherosclerosis

Local Bone Marrow RAS

Hypertension

Neoplastic Hematopoiesis

FIGURE 7.1 The impact of the local bone marrow renin-angiotensin system (RAS) on the definitive blood cell production, neoplastic hematopoiesis, atherosclerosis, and systemic hypertension. SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2, AcSDKP: N-acetyl-serylaspartyl-lysyl-proline, CFU-GM: Colony-forming unit granulocyte-macrophage, ACE: Angiotensin-converting enzyme, Ang (1e7): Angiotensin (1e7), Ang II: Angiotensin II, Ang I: Angiotensin I, MasR: Mas receptor, AT2R: Angiotensin II type 2 receptor, AT1R: Angiotensin II type 1 receptor, ANPEP: Alanyl aminopeptidase, HSC: Hematopoietic stem cell.

2. Local bone marrow renineangiotensin system in hematopoiesis Blood cell production is affected by locally active ligand peptides, mediators, receptors, and signaling pathways of the hematopoietic bone marrow autocrine/paracrine RAS [28,29]. Local bone marrow RAS controls the hematopoiesis, erythropoiesis, myelopoiesis, monocytic and lymphocytic lineages, thrombopoiesis, and other stromal cellular elements [30]. Local bone marrow RAS also has a role in primitive embryonic hematopoiesis [31]. ACE is found on the surface of endothelial and hematopoietic cells [32]. ACE marks early hematopoietic precursor cells and long-term blood-forming CD34þ bone marrow cells [32]. Moreover, the local autocrine tissue bone marrow RAS has a role in neoplastic hematopoiesis [19]. Important RAS elements such as renin, ACE, Ang II, and angiotensinogen have been found in leukemic blast cells [33,34]. The local tissue RAS affects tumor growth and metastases in an autocrine and paracrine manner by the alteration of many carcinogenic

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factors, such as angiogenesis, apoptosis, cellular proliferation, immune responses, cell signaling, and extracellular matrix formation [35]. The role of Ang II in the development of all lineages in the bone marrow is well known in the literature. When Ang II was given externally, the colony development from hematopoietic stem cell to CFU-GM and CFU-GEMM was increased [36]. TNF-alpha secretion is controlled by Ang II as well as its production from bone marrow by the regulation the monocytic lineages [37]. In the bone marrow microenvironment, production of arachidonic acid is controlled by the local Ang II [37]. Arachidonic acid is produced with the stimulation of Ang II, and then it transfers to a cellular section of bone marrow [37]. Afterward, arachidonic acid plays the role of a signaling molecule; therefore, it controls the secretion or inhibition of hematopoietic precursors. Arachidonic acid has eicosanoid metabolites, and these two substances have functions in the control of hematopoietic pathways [37]. Local bone marrow RAS has a considerable role on the hematopoietic mechanisms, particularly on myeloid and erythroid cells [7,21,38]. Local bone marrow RAS has effects through the control of significant peptides, which regulates hematopoiesis. With the stimulation of ACE, Ang I changes to Ang II, while bioactive SP, Ac-SDKP, and Ang 1e7 have been deactivated by ACE. Additionally, throughout this course, substance P is secreted from nerve endings, which are launched against the bone marrow microenvironment. Bone marrow stromal and hematopoietic cells produce RAS peptides by the AT1 and NK1 receptors, which control the effect of Ang II and SP, respectively. Moreover, the receptor of Ang 1e7, MAS is present in bone marrow stroma [36]. The roles of the local bone marrow RAS within the context of primitive, definitive, and neoplastic hematopoiesis are well defined in the literature [38]. In the treatment of neoplastic hematological diseases, the local RAS elements may be a therapeutic target [39,40].

3. Local bone marrow renineangiotensin system in neoplastic hematopoiesis The presence of a local RAS specific to the hematopoietic bone marrow microenvironment had been proposed two decades ago [7]. ACE, ACE2, AGT, AGTR1, AGTR2, AKR1C4, AKR1D1, ANPEP, ATP6AP2, CMA1, CPA3, CTSA, CTSD, CTSG, CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP21A2, DPP3, EGFR, ENPEP, GPER, HSD11B1, HSD11B2, IGF2R, KLK1, LNPEP, MAS1, MME, NR3C1, NR3C2, PREP, REN, RNPEP, and THOP1 are some of the RAS molecules, which are locally found in the bone marrow microenvironment [41]. Hematopoietic niche, myelopoiesis, erythropoiesis, thrombopoiesis, and other cellular lineages are controlled by the local bone marrow RAS [42e46]. Local bone marrow RAS has an important role in hematopoietic stem cell biology and microenvironment. The proliferation, differentiation, and engraftment of hematopoietic stem cells are

4. Local bone marrow renineangiotensin system in atherosclerosis

controlled by angiotensin II [47]. Ang II may be a factor that stimulates the proliferation of hematopoietic progenitors [25]. Proliferation of CD34þ cells is stimulated by the Mas receptor or ACE2 [48]. A progenitor that expresses renin is found in bone marrow during development [49]. The adhesion of MNCs and CD34þ cells is increased by angiotensin II and the migration and proliferation of CD34þ cells are stimulated by angiotensin II [48]. Renin cells in hematopoietic organs are precursor B cells [49]. RBP-J is necessary for renin cell to differentiate. Deletion of RBP-J in the renin-expressing progenitors enriches the precursor B cell gene program and constrains lymphocyte differentiation. Deletion of RBP-J in renin lineage cells results in enhanced cell cycle progression and stimulated cell proliferation [49]. Mutant renin-expressing hematopoietic precursors may lead to leukemia [49]. Mutant cells go through a neoplastic transformation, and mice have a highly aggressive B cell leukemia with multiorgan infiltration and early mortality [49]. Several functions of blood cells such as apoptosis, cellular proliferation, intracellular signaling, mobilization, angiogenesis, and fibrosis within the cytokine network are controlled by different biological conditions during the development of blood cells [25,50e55]. Recent developments about the actions of local bone marrow RAS in the genesis of leukemia and other malignancies molecules are well defined in the literature [56]. RAS in bone marrow is proposed to increase cellular proliferation and differentiation. Renin in myeloid blast cells’ cytosol has been identified, and some blast cells from some types of AML have also contained renin. 77% of AML and 100% of ALL cases were found as renin positive [57]. Renin expression vanished with hematological remission and returned with relapse [58]. ACE inhibitors and the AT1 receptor antagonist have an antiproliferative and apoptotic activity on leukemic cells [58]. Likewise, a relationship has been detected between ACE and bone marrow blast count [59]. ACE insertion/deletion gene polymorphisms in patients with hematological neoplasia were analyzed together with acute and chronic leukemia, myelodysplastic syndrome, and multiple myeloma. 80.4% of the patients had an insertion/deletion II genotype versus 55.9% in the control group, and there were 3.2 times amplified disease risk in the presence of the insertion allele [60].

4. Local bone marrow renineangiotensin system in atherosclerosis RAS plays a crucial role in the control of blood pressure, blood flow, fluid volume, and electrolyte balance, and excess stimulation of this system leads to the pathogenesis of a different of clinical situations, including onset, progression, and outcome of atherosclerosis [61]. Local hematopoietic bone marrow RAS has a role in growth, production, proliferation differentiation, and function of hematopoietic cells [21]. Ang II is the main active peptide of the RAS, and it controls cellular growth in different tissues in pathobiological states. Ang II has a role in vascular remodeling,

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acting as a bifunctional growth factor that increases secretion of growth factors and vasoactive agents [62,63]. RAS, especially Ang II and Ang II type 1 receptor (AT1R), has important proinflammatory and proatherogenic effect on the vessel wall, leading to development of atherosclerosis [64,65]. Inflammatory cells that are present in atherosclerotic lesions are generally originated from bone marrow. Other than a wide range of data clarified the presence of a functional local BM RAS. Angiotensin II, by acting together with AT1 receptor, enhances erythroid differentiation in the bone marrow [44]. Ang II-stimulated erythroid progenitors made considerably higher numbers of burst-forming unit-erythroid (BFU-E) colonies in normal human erythropoiesis. The local RAS of the bone marrow could play significant roles within the process of atherosclerosis [66]. Ang II-AT1R pathway in bone marrow leads to atherosclerotic development in the hypercholesterolemic mice. AT1R in bone marrow cells have a role in the pathogenesis of atherosclerosis according to the analyses of numerous bone marrow chimeric mice whose bone marrow cells were positive or negative for AT1R [37,67]. Therefore, AT1R blocking not only in vascular cells but also in the bone marrow could be a significant treatment method to inhibit atherosclerosis [66,68e70]. Strawn et al. suggested a lipide angiotensin system relation within the bone marrow that is responsible for the predisposition of immune cells to home to coronary arteries and lead to atherosclerosis [71]. This study favored a positive modifying effect of plasma LDL on AT1R-mediated hematopoietic stem cell differentiation and the development of proatherogenic monocytes that can describe in part hypercholesterolemia-induced inflammation as well as the antiinflammatory and antiatherosclerotic effects of AT1R blockers. This viewpoint combines the previous lipid hypotheses and lets for an immunological stimulation perception that starts as early as changes in the bone marrow, which leads to the production of activated circulating monocytic phenotypes that involve in atherogenesis. The “bone marrow response-to-lipid” hypothesis integrates the knowledge that proatherogenic features of hematopoietic and nonhematopoietic progenitors are determined by the local actions of modified LDL on the expression of local RAS genes [72]. Moreover, the role and function of local bone marrow RAS in the pathogenesis of atherosclerosis is well defined in the literature [73]. Ang II may compromise the structural integrality of the endothelial barrier through stimulation of endothelial cell apoptosis. Inflammatory response in the vascular intimal layer including macrophages and T lymphocytes by RAS-stimulated oxidative stress and hyperthrombotic state leads to oxidative lipoprotein modification, smooth muscle cell migration from the media into the intima, proliferation, and transformation from a contractile to a synthetic phenotype. Although the earlier phases can remain subclinical, this phase of the atherosclerotic process results in an important decrease in the vessel lumen. AT1aR present on vascular cells and also on BM-derived cells has important effects on the atherosclerotic plaque pathogenesis, at least moderately by quickening the infiltration of BM-derived inflammatory cells in the vessel wall. Clarifying the variety of intracellular Ang II synthesis pathways could lead to emerging therapeutic interventions, and inhibition of AT1R in vascular cells and also in bone marrow may

5. Local bone marrow renineangiotensin system in hypertension

be a significant strategy to avoid development and destabilization of atherosclerotic plaques.

5. Local bone marrow renineangiotensin system in hypertension Circulating RAS and local paracrineeautocrineeintracrine tissue-based RAS have significant roles underlying numerous pathobiological events. Proinflammatory, profibrotic, and prothrombotic effects related with local RAS stimulation have been found at cellular and molecular levels [74]. RAS-modifying pharmacotherapy eventually leads to regenerative progenitor cell treatment in the context of endothelial cell injury and regeneration to improve regeneration of the vascular endothelium [75]. Local hematopoietic bone marrow RAS represents the place of crossinteraction between vascular biology and cellular events from embryogenesis to definitive hematopoiesis underlying vascular atherosclerosis [76]. The bone marrow microenvironment also has Mas receptors that regulate the simulative role of Ang 1e7 on hematopoietic stem cells [36]. Ang 1e7 is secreted from Ang II or Ang I with the stimulation of ACE2 [77]. Several tissues and organs also are also in relationship with RAS. The leukocytes produce immunoreactive angiotensinogen species, which are capable of secreting angiotensin in the basal state or after incubation with renin [78]. The importance of the role of RAS in atherosclerosis and hypertension was showed by novel bidirectional central nervous system RASd bone marrow RAS communications [73]. The main initiator and driver of atherosclerosis is the myeloid cells produced by hematopoietic bone marrow RAS [73]. Oxidative stress and inflammation are the main mechanisms of action of Ang II on atherosclerosis [79]. Inflammatory cells in atherosclerotic lesions are mainly produced from bone marrow [44]. Macrophages in the atherosclerotic lesions have angiotensin peptides by which RAS blockers decrease monocyte stimulation and adherence [80]. Moreover, vascular biology by the context of inflammation and neoplasia is also controlled by local tissue RAS [81]. There is a close relationship between the autonomic nervous system and bone marrow cells. This association between bone marrow stromal cells, hematopoietic stem cell, and nerve terminals has been described as the “neuroreticular complex” [82,83]. A characteristic feature of early hypertension is endothelial dysfunction [84]. Bone marrowerelated endothelial progenitor cells contribute in the healing of injured endothelium. Several studies have reported that endothelial progenitor cells numbers and functions are lower in cases with hypertension and cardiovascular disease [85e87]. Interlink between autonomous nervous system and bone marrow vasculature could be an important mechanism of the pathophysiology of hypertension. Norepinephrine has a vasoconstrictor effect in the bone marrow and have an important role in controlling blood flow [88]. Prohypertensive signals, for example, excess Ang II, lead to neurovasculareglial inflammation in the cardioregulator areas

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of the brain [81]. Dysfunctional autonomous nervous system output is presented by increase in the sympathetic and a decrease in the parasympathetic impulse to the periphery, including bone marrow [81]. This course stimulates an increase in peripheral Ang II [81]. Therefore, it leads to a permanent increase in the inflammatory cells and a reduction in the endothelial progenitor cells [81]. Increased inflammatory cells results in vascular and tissue damage, while decreased endothelial progenitor cells lead to repair of this harm, resulting in cardiorenal pathology. Bone marrow plays a significant role in neurogenic hypertension. Memory T cells are in the bone marrow. T cell stimulation has an important role in hypertension [89]. The bone marrow is the main source of endothelial progenitor cells, which have an important role in endothelial repair in arterial or renal injury [75]. Chronic elevation in bone marrow norepinephrine may block the function of endothelial progenitor cells, and this mechanism could be important in the terms of hypertension. The interactions of circulating and local angiotensin systems, particularly local bone marrow RAS, in the vascular pathobiological microenvironment of central nervous system is well defined in the literature [76].

6. Local bone marrow renineangiotensin system and COVID-19 syndrome COVID-19 syndrome has three clinicopathological phases, which are initial, propagating, and complicating phase [90]. Each of these phases has different features in relation to distinct immunogenomic mechanisms effecting critical tissue-based RAS genes [91]. ACE2 molecule is the essential and important receptor of SARS-coronaviruses to invade the target cells [92]. Binding to the ACE2 receptor and utilizing a spike protein (S) for attachment is necessary for the SARS-CoV-2 to enter to human cells. The viral S protein must be primed by transmembrane protease 2 (TMPRSS2) to stimulate contact with ACE2 receptor and the subsequent fusion of viral and cellular membranes [92]. ACE2 receptor is presented on the surface of hematopoietic stem/progenitor cells within the context of local bone marrow RAS that characterizes a target for the SARS-CoV-2 attack on bone marrow hematopoiesis [93]. Pulmonary ACE2 has an important effect in protecting the lung from Ang II-AT1R-stimulated inflammation because not only is there a local pulmonary RAS but also the lung is main organ for transformation of inactive Ang I to Ang II [94,95]. For that reason, loss of the ACE2, after the binding of SARS-CoV-2, not only exposes the lung tissue epithelium to locally secreted Ang II as well as to Ang II secreted in the lung from circulating Ang I. SARS-CoV is a cousin of SARS-CoV-2, and ACE2 relations have been broadly investigated in lung microenvironment [96e98]. The initial study is conducted by Kuba et al., which focuses on the importance of ACE2 for SARS-CoV infections in vivo [92]. This study proposed that SARS-CoV infections result within the ACE2 downregulation by the binding of the SARS-CoV spike protein to ACE2. Therefore, the SARS-CoV family, including

6. COVID-19 syndrome

SARS-CoV-2, uses ACE2 as an important and essential receptor to invade target host cells. We identified the whole-genome expression data of the lung epithelial cells infected with SARS-CoV for 12, 24, and 48 h were investigated, and a total of 15 RAS family and 29 immune genes were found to be related with the exposure time to the virus [91]. These results favor the important effect of the RAS genes on the initiation of the infections triggered by coronavirus family members in the lung. Using monoclonal anti-Ang II and antireceptor-binding domain antibodies, antibody cross-binding between Ang II and Spike/receptor-binding domain may occur, even if weakly, favoring some structural homology between Ang II and certain epitopes of Spike/receptor-binding domain [99]. Therefore, SARS-CoV-2 virus is likely to spread to lungs not only ACE2 but also local pulmonary RAS system. The relationship of hematopoietic RAS with other tissue RAS systems is well defined in the literature [38,73,76,100]. Kucia et al. proposed that ACE2 receptor is presented on the surface of hematopoietic stem/progenitor cells, for SARSCoV-2 viral entry [93]. In their analysis, CD34 þCD133 þ lineCD45d, CD34 þLinCD45 þ HSCs, and CD34 þ CD133 þ KDR þ CD31 þ EPC cells were detected for the expression of ACE2 and the SARS-CoV-2 entry stimulating transmembrane protease TMPRSS2 at the mRNA level and by FACS at the protein level. Those cells were exposed to the NCP-CoV (2019-nCoV) spike protein. Eventually, ACE2 receptor and SARS-CoV-2 entry-facilitating transmembrane protease TMPRSS2 are likely to be presented by all types of hematopoietic stem cells. Ihlow et al. proposed that severe lymphocyte depletion and overactivation of the adaptive immune system frequently detected during the COVID-19 progression are triggered by the significant loss of B cells related with viral SARS-CoV-2 burden [101]. A multicenter study conducted by Deutsche COVID-19 OMICS initiative revealed the increase of HLA-DRhiCD11chi inflammatory monocytes with an interferon promoted gene signature in mild COVID-19, and dysfunctional mature neutrophils, HLA-DRlo monocytes, and occurrence of neutrophil precursors as evidence of emergency myelopoiesis in severe COVID-19 patients [102]. Therefore, severe COVID-19 infection is related with extensive changes in the myeloid cell compartment providing a comprehensive understanding into the systemic immune response to SARS-CoV-2 infection. After the respiratory tract involvement by controlling molecular mechanisms related with ACE2 receptor in the lungs, the virus may alter the local BM RAS, also. Consequently, BM hematopoietic stem and progenitor cells may stimulate the dissemination of the virus to different circulating and local angiotensin systems including local adipose tissue RAS, local cardiac RAS, local pancreatic RAS, and local renal RAS. That pathobiologic sequence eventually may lead to a multisystemic immune dysfunction. Lefranc¸ais et al. showed that the lung has an array of hematopoietic progenitors including short-term HSCs, multipotent progenitors 2/3/4, and myeloerythroid progenitor populations, which cannot be morphologically differentiated from bone marrow primitive hematopoietic stem cells [103]. On the other hand, thrombopoietin stimulation may lead to platelet secretion in the pulmonary vasculature [104]. Haznedaroglu et al. analyzed local thrombopoietin concentrations inside the pulmonary artery and associated vessels in patients with and

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without pulmonary hypertension [105]. They proposed that thrombopoietin concentration inside the pulmonary artery was higher than the thrombopoietin concentrations in the right and left ventricles in cases with pulmonary hypertension. Eventually, bone marrow and lung tissue are likely in a harmony in hematopoiesis under the control of tissue RAS. On the other hand, pulmonary inflammation is the major event in the lung damage of COVID-19 [106]. Localized inflammation in the COVID-19 cases may lead to cause decrements in the anticoagulant pathways. Similarly, the inflammatory mechanism may result in the increase of endothelial cells expressing tissue factor, producing molecules. All of these pathobiological prothrombotic events are controlled by the monocytes, platelets, neutrophils, and platelet-leukocyte aggregates, and all of these are of hematopoietic bone marrow origin. ACE2 increases the hydrolysis of angiotensin II to its metabolite, angiotensin 1e7, and angiotensin I to angiotensin 1e9 to avoid tissues from injuries [107]. RAS modulating agents for blocking immunogenomic development of COVID-19 syndrome may be a rational choice for inhibiting ACE2, which is the cellular target of SARS-CoV-2 [108]. RAS-modifying agents such as soluble ACE2, angiotensin (1e7), TXA127, and MAS receptor agonists could be beneficial by blocking the entry of SARS-CoV-2 into the human cells, as well as by inhibiting the dissemination of the virus from local pulmonary RAS to other local tissue RAS systems including bone marrow. Soluble ACE2 is a new agent that has two effective mechanisms for SARS-CoV-2. Soluble ACE2 is able to hold to viral spike protein so that it can block SARS-CoV-2. RAS hyperactivation and increased angiotensin II concentrations could harm multiple organs, such as the lungs, kidneys, and heart and soluble ACE2, which can prevent this type of injury [109,110]. Intravenous delivery of soluble ACE2 inhibits the systemic dissemination of the virus from the lung to other organs [110]. Angiotensin-(1e7) is one of the major modifiers of the RAS, which can undo various deleterious effects led by angiotensin II. Angiotensin 1e7 stimulates RAS axis to avoid a decrease in blood pressure, and the ACE level will increase and the ACE2 level will decrease because of the accumulation of angiotensin 1e7 [111,112]. Providing high levels of angiotensin 1e7 and ACE while decreasing inflammatory bradykinin will be protective against the entry point of the virus into the host cells which is ACE2 [113]. There are ongoing clinical trials regarding the safety, efficacy, and clinical importance of angiotensin-(1e7) in COVID-19 cases with or without respiratory failure requiring mechanical ventilation [114]. Mas is a G proteinecoupled receptor for Ang-(1e7); it has led to identify Ang-(1e7) as a biologically active component of the RAS [115]. Mas receptor stimulation has a significant role to compete the deleterious effects stimulated by an excess increase in Ang II/AT1 receptor in various clinical conditions as shown by Santos et al. [116]. Furthermore, the stimulation of the Mas receptor with Mas analogs may have critical role controlling the inflammatory reactions facilitated by SARS-CoV-2 [114,117]. Also, ANPEP gene pathway has been offered as a potential target for the vaccine development [90]. RAS genes are critical at the initiation of the infections initiated by coronavirus family members and can have an important association with the exchange of immune genes in due clinical course following the infection.

6. COVID-19 syndrome

Table 7.1 Hematopoietic bone marrow renineangiotensin system in health and disease. Aim

Current knowledge

Definitive hematopoiesis

- Ang II increases the colony development from hematopoietic stem cell to CFU-GM and CFU-GEMM [36]. - TNF-alpha secretion is controlled by Ang II as well as its production from bone marrow by the regulation the monocytic lineages [37]. - Production of arachidonic acid is controlled by the local Ang II [37]. - Bone marrow stromal and hematopoietic cells produce RAS peptides by the AT1 and NK1 receptors that control the effect of Ang II and SP [36]. - The receptor of Ang 1e7, MAS, is present in bone marrow stroma [36]. - Proliferation of CD34þ cells is stimulated by the mas receptor or ACE2 [48]. - The adhesion of MNCs and CD34þ cells is increased by angiotensin II as well as the migration and proliferation of CD34þ cells are stimulated by angiotensin II [48]. - RBP-J is necessary for renin cell to differentiate. Deletion of RBP-J in the renin-expressing progenitors enriches the precursor B cell gene program and constrains lymphocyte differentiation. Deletion of RBP-J in renin lineage cells results in enhanced cell cycle progression and stimulated cell proliferation [49]. Mutant reninexpressing hematopoietic precursors may lead to leukemia [49]. - 77% of AML and 100% of ALL cases were found as renin positive in a previous study [57]. Renin expression vanished with hematological remission and returned with relapse [58]. - ACE insertion/deletion gene polymorphisms in patients with hematological neoplasia were analyzed together with acute and chronic leukemia, myelodysplastic syndrome, and multiple myeloma. 80.4% of the patients had an insertion/deletion II genotype versus 55.9% in the control group, and there were 3.2 times amplified disease risk in the presence of the insertion allele [60]. - RAS, especially Ang II and Ang II type 1 receptor (AT1R), has important proinflammatory and proatherogenic effect on the vessel wall, leading to development of atherosclerosis [64,65]. - The local RAS in bone marrow plays important roles in atherosclerosis [66]. Ang IIeAT1R pathway in bone marrow leads to atherosclerotic development in the hypercholesterolemic mice. - AT1R blocking not only in vascular cells but also in the bone marrow could be a significant treatment method to inhibit atherosclerosis [66,68e70]. - A lipideangiotensin system relation within the bone marrow that is responsible for the predisposition of immune cells to home to coronary arteries and lead to atherosclerosis [71]. - The “bone marrow response-to-lipid” hypothesis integrates the knowledge that proatherogenic features of hematopoietic and

Neoplastic hematopoiesis

Atherosclerosis

Continued

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Table 7.1 Hematopoietic bone marrow renineangiotensin system in health and disease.dcont’d Aim

Hypertension

Current knowledge

-

-

-

-

-

COVID-19

-

-

-

-

nonhematopoietic progenitors are determined by the local actions of modified LDL on the expression of local RAS genes [72]. Proinflammatory, profibrotic, and prothrombotic effects related with local RAS stimulation have been found at cellular and molecular levels [74]. The main initiator and driver of atherosclerosis is the myeloid cells produced by hematopoietic bone marrow RAS [73]. Inflammatory cells in atherosclerotic lesions are mainly produced from bone marrow [44]. Macrophages in the atherosclerotic lesions have angiotensin peptides by which RAS blockers decrease monocyte stimulation and adherence [80]. Vascular biology by the context of inflammation and neoplasia is also controlled by local tissue RAS [81]. Association between bone marrow stromal cells, hematopoietic stem cell, and nerve terminals has been described as the “neuroreticular complex” [82,83]. A characteristic feature of early hypertension is endothelial dysfunction [84]. Interlink between autonomous nervous system and bone marrow vasculature could be an important mechanism of the pathophysiology of hypertension. Norepinephrine has a vasoconstrictor effect in the bone marrow and have an important role in controlling blood flow [88]. The bone marrow is the main source of endothelial progenitor cells, which have an important role in endothelial repair in arterial or renal injury [75]. ACE2 receptor is presented on the surface of hematopoietic stem/progenitor cells within the context of local bone marrow RAS that characterizes a target for the SARS-CoV-2 attack on bone marrow hematopoiesis [93]. The relationship of hematopoietic RAS with other tissue RASs is well defined in the literature [38,73,76,100]. ACE2 receptor is presented on the surface of hematopoietic sstem/progenitor cells, for SARS-CoV-2 viral entry [93]. Severe lymphocyte depletion and overactivation of the adaptive immune systems frequently detected during the COVID-19 progression are triggered by the significant loss of B cells related with viral SARS-CoV-2 burden [101]. Increase of HLA-DRhiCD11chi inflammatory monocytes with an interferon promoted gene signature in mild COVID-19, and dysfunctional mature neutrophils, HLA-DRlo monocytes, and occurrence of neutrophil precursors as evidence of emergency myelopoiesis in severe COVID-19 patients [102]. The lung has an array of hematopoietic progenitors including short-term HSCs, multipotent progenitors 2/3/4, and myeloerythroid progenitor populations, which cannot be morphologically

7. Conclusion and perspectives

Table 7.1 Hematopoietic bone marrow renineangiotensin system in health and disease.dcont’d Aim

Current knowledge

-

-

-

-

-

-

-

-

-

differentiated from bone marrow primitive hematopoietic stem cells [103]. Antibody cross-binding between Ang II and spike/receptorbinding domain may occur, even if weakly, which can favor some structural homology between Ang II and certain epitopes of spike/ receptor-binding domain [99] Thrombopoietin stimulation may lead to platelet secretion in the pulmonary vasculature [104]. RAS modulating agents for blocking immunogenomic development of COVID-19 syndrome may be a rational choice for inhibiting ACE2, which is the cellular target of SARS-CoV-2 [108]. Soluble ACE2 inhibits the systemic dissemination of the virus from the lung to other organs [110]. Angiotensin 1e7 stimulates RAS axis to avoid a decrease in blood pressure, and the ACE level will increase and the ACE2 level will decrease because of the accumulation of angiotensin 1e7 [111,112]. Providing high levels of angiotensin 1e7 and ACE while decreasing inflammatory bradykinin will be protective against, the entry point of the virus into the host cells which is ACE2 [113]. There are ongoing clinical trials regarding the safety, efficacy, and clinical importance of angiotensin-(1e7) in COVID-19 cases with or without respiratory failure requiring mechanical ventilation [114]. Mas is a G proteinecoupled receptor for Ang-(1e7); it has led to identify Ang-(1e7) as a biologically active component of the RAS [115]. Mas receptor stimulation has a significant role to compete the deleterious effects stimulated by an excess increase in Ang II/AT1 receptor in various clinical conditions [116]. The stimulation of the mas receptor with mas analogs may have a critical role controlling the inflammatory reactions facilitated by SARS-CoV-2 [114,117]. ANPEP gene pathway has been offered as a potential target for the vaccine development [90]

7. Conclusion and perspectives In this chapter, we have focused on the hematopoietic bone marrow RAS in health and disease. The role of hematopoietic bone marrow RAS in health and disease is summarized in Table 7.1. Local RAS has major role in the definitive and neoplastic hematopoiesis. Also, local bone marrow RAS, hematopoietic cells, and COVID-19 are in relationship with various molecular mechanisms. Moreover, local pulmonary RAS and bone marrow RAS are associated with each other, and this relationship is important regarding the impact of local pulmonary RAS on COVID-19 syndrome.

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CHAPTER 7 Hematopoietic bone marrow renin-angiotensin system

Multiorgan involvement of COVID-19 syndrome in associations with the local RASs is depicted in Fig. 7.2. The recent pandemic of SARS-CoV-2 is a disaster for all people in the world. Organ-based RAS genes have role in the beginning of the infections led by coronavirus family members and could have a significant association with the exchange of immune genes in the course of following the infection [91]. Preventing immunogenomic progression of COVID-19 syndrome by blocking pathobiological harmony between local pulmonary RAS and bone marrow RAS with RAS modulating agents offers a novel perspective. The RAS modulating agents

FIGURE 7.2 Multiorgan involvement of COVID-19 syndrome in associations with the local renineangiotensin systems (RAS). SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; AcSDKP, N-acetyl-serylaspartyl-lysyl-proline; CFU-GM, colony-forming unit granulocyte-macrophage; ACE, angiotensin-converting enzyme; Ang (1e7), angiotensin (1e7); Ang II, angiotensin II; Ang I, angiotensin I; MasR, Mas receptor; AT2R, angiotensin II type 2 receptor; AT1R, angiotensin II type 1 receptor; ANPEP, alanyl aminopeptidase; HSC, hematopoietic stem cell.

References

such as soluble ACE2, angiotensin (1e7), TXA127, and MAS receptor agonist could block the entry of SARS-CoV-2 into human cells, and moreover, they could inhibit the dissemination of the virus from local pulmonary RAS to other local tissue RAS systems such as bone marrow RAS. The RAS genes in various organs are involved in the dissemination of COVID-19; therefore, the mechanism and role of organ-based RAS system are needed to be comprehensively investigated to overcome the viral infections. Also, local bone marrow RAS is associated with the neoplastic diseases. All of these knowledge accumulation favors that the organbased local RASs could be the key to deal with various neoplastic and viral diseases. Future experimental and clinical research studies are needed to clarify the tissuebased RASs.

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CHAPTER

8

Angiotensin II as a mediator of renal fibrogenesis

Ivonne Loeffler, Gunter Wolf Department of Internal Medicine III, Jena University Hospital-Friedrich Schiller University, Jena, Germany

1. Introduction Chronic kidney disease is increasing worldwide [1]. Renal diseases, irrespective of the primary etiology, progress to end-stage renal disease with an irreversible loss of renal tissue [2,3]. Glomerulosclerosis, fibrosis of the tubulointerstitial microenvironment, and tubular atrophy all constitute the major morphological correlates of such end-stage kidneys. Deposition of extracellular matrix (ECM) proteins including fibronectin, collagen types I, III, and IV is an important component of the scarring observed during the evolution of glomerulosclerosis and tubulointerstitial fibrosis [4]. Until the introduction of SGLT2 inhibitors [5], intervention to inhibit the renine angiotensin system (RAS) was the only therapeutic agent to interfere with this progression of chronic kidney disease toward end-stage, dialysis-dependent chronic kidney disease [6]. Starting with the landmark studies of Anderson and coworkers [7] showing the superiority of angiotensin-converting enzyme (ACE) inhibitors in halting the progression of renal disease, many studies have demonstrated that interference with the RAS can protect kidneys. Although recent clinical studies have demonstrated that also aldosterone plays a major role in the progression of CDK [8], angiotensin II (Ang II) is likely the major culprit. Therefore, this chapter will review the role and function of Ang II in the kidney and will particularly focus on its role in fibrogenesis beyond the “classical” renal actions of Ang II on hemodynamics and tubular transport. However, Ang II has many diverse effects on renal cells, which are depicted in Fig. 8.1. In addition, the pathophysiological effects, such as stimulation of inflammation and fibrogenesis, are difficult to separate and work in concert to damage the kidney.

2. The intrarenal renineangiotensin system Over the past two decades, local RASs have been described operating independently from their systemic counterparts [9]. For example, expression of local RAS components has been found in the brain where they are involved in the regulation of thirst and salt appetite (see other chapters in this book). A local RAS including all its Angiotensin. https://doi.org/10.1016/B978-0-323-99618-1.00011-8 Copyright © 2023 Elsevier Inc. All rights reserved.

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FIGURE 8.1 Ang II is a multifunctional cytokine that exhibits many properties in the kidney, beyond its classical function as a hemodynamic mediator.

components is also present in renal proximal tubular cells [10]. Angiotensinconverting enzyme (ACE) is present at the luminal brush border sites and also likely intracellular [4]. Micropuncture studies have provided strong evidence that proximal tubular cells actively produce Ang II and also secrete angiotensinogen into the urine where it can be measured in relatively high concentrations, whereas Ang II is quickly degraded [11]. It is also obvious that this intratubular RAS may interact with components of the systemic (circulating) RAS. Intraluminal angiotensinogen may be converted in the distal tubules to Ang II and stimulates sodium channels independently of aldosterone [11]. Hyperglycemia and proteinuria through reabsorption of proteins/peptides in the proximal tubule stimulate local Ang II synthesis, likely by oxygen species as signal transducers [12]. Moreover, renal injury activates the local RAS directly and indirectly. Interestingly, reduction in calcitriol (for example, by reduced tubular 1e25 hydroxylation as an effect of tubular damage) can stimulate renin transcription accompanied by local increase of Ang II demonstrating an indirect activation [13]. Of most clinical relevance is the fact that complete systemic inhibition of the Ang II formation by ACE inhibitors in the used clinical doses is not accompanied by a significantly reduced intrarenal Ang II production [14]. Intact Ang II can be intracellularly found in endosomes derived from receptor-mediated endocytosis [15]. This may likely contribute to inflammation and fibrogenesis, because observations have demonstrated that Ang II can be translocated into the nucleus where it directly regulates the gene transcription [16].

2. The intrarenal renineangiotensin system

2.1 “Classical” actions of Ang II in the kidney Landmark micropuncture studies have shown that Ang II preferentially raises efferent glomerular resistance [17]. The differential mechanisms of the various degree of vasoconstriction in afferent versus efferent glomerular capillaries are subject of controversy but may include concomitant induction of vascular dilatory factors such as prostaglandins and/or nitrogen monooxide (NO) by Ang II in afferent, but not in efferent arterioles. The consequence is an increase in the glomerular capillary filtration pressure that results in a protected glomerular filtration rate despite an Ang IIinduced decrease in renal plasma flow (Fig. 8.2) [17]. Angiotensinogen knockout mice exhibited a marked decline in glomerular filtration rate in response to salt restriction demonstrating the importance of Ang II for normal glomerular filtration rate [18]. The pioneering work by Blantz and colleagues revealed that Ang II has also important effects on the product of the local effective permeability of the capillary wall (k) and the surface area available for filtration (this product is called Kf) [19]. Ang II reduces the permeability k and the surface area through binding to endothelial and mesangial cells as well as podocytes. As a consequence, the filtration surface is reduced, presumably by constriction of mesangial cell, whereas Ang II significantly changes the molecular composition of the foot processes of podocytes [20]. Constriction of the efferent arterioles by Ang II increases peritubular capillary colloid osmotic pressure through a decrease in renal blood flow and an increase in filtration fraction [17]. Since these changes increase interstitial fluid colloid osmotic

FIGURE 8.2 Ang II increases glomerular filtration pressure by causing vasoconstriction of afferent and efferent arterioles. Please note that the vasoconstriction is greater in efferent vessels compared with afferent arterioles, thereby increasing resistance and glomerular pressure. This is likely due to concomitant induction of vasodilative factors (NO, prostaglandins) in afferent arterioles by Ang II. Although these mechanisms help to initially maintain glomerular filtration rate after loss of nephrons, it becomes in the long-term run contraproductive, because the high single nephron filtration rate further damages kidney structures inducing proteinuria. Moreover, the high local Ang II concentration fosters inflammation and fibrosis.

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pressure and tend to reduce interstitial fluid hydrostatic pressure, Ang II indirectly increases the driving force for fluid reabsorption across tubular cells [17]. In proximal tubular cells, Ang II stimulates luminal sodiumehydrogen exchange and bicarbonate reabsorption as well as basolateral sodiumebicarbonate and sodiumepotassium exchange [21]. Moreover, Ang II increases sodium, chloride, and bicarbonate reabsorption in the loop of Henle and even more distal nephron fragments [22]. Hostetter and colleagues found an increase in glomerular capillary pressure in many animal models of progressive nephron loss [23]. Although these adaptive mechanisms may maintain indeed renal function in the early phase of chronic renal injury, glomerular hypertension and hyperfunction are ultimately detrimental to renal function and structure [24]. An increase in capillary pressure may directly stimulate in glomerular cells through mechanical forces injury, proliferation, and production of extracellular matrix [25].

3. The renal renineangiotensin system: much more complex than previously thought It is generally accepted that ACE is the key enzyme in generation of Ang II from angiotensin I. However, it is not the only enzyme responsible for Ang II generation (see Fig. 8.3). Other, more recently described, Ang II-generating enzymes such as the serine protease chymase may be responsible for more than 80% of Ang II formation, at least in the heart, and more than 60% in vessels [26]. This is of major clinical importance because ACE inhibitors do not reduce chymase activity. Moreover, an upregulation of chymase, especially in proximal tubules, has been found in renal biopsies of patients with diabetic nephropathy [26,27]. This important observation suggests that, under certain pathologic conditions, an upregulation of chymase occurs and may increase in local Ang II generation, an effect not inhibited by ACE inhibitors. In addition, mechanical stress of podocytes (for example, occurring during hyperfiltration) stimulates local Ang II synthesis by non-ACE pathways, presumably involving chymase [28]. Another enzyme involved in generating active Ang II is the chymostatin-sensitive angiotensin II-generating enzyme (CAGE) [29]. An enzyme similar to ACE has been identified, called angiotensin-converting enzyme 2 (ACE2) [30]. The ACE2 gene maps to the human X chromosome, and the amino-terminal domain of ACE2 shares approximately 40% sequence identity with ACE [31] and is the primary receptor for the spike proteins of various coronaviruses [32,33]. ACE2 is found predominantly in vascular endothelial cells, including those of the kidney. This finding may explain why COVID-19 predominantly damages these organs. ACE2 has been also localized renal in podocytes [34] and tubular cells [35]. The major physiological function of ACE2 is associated with its metalloprotease activity. ACE2 is phosphorylated at Ser680 on its extracellular domain inhibiting ubiquitination, thereby increasing enzyme stability. AMP-

3. The renal renineangiotensin system

FIGURE 8.3 Overview of the complexity of the RAS with its various components, degradation products, which are active by themselves, and multiple receptors. However, this system has become increasingly complicated with other ways of Ang II generation besides ACE (chymase, CAGE), a second form of ACE (ACE2), and other peptides such as Ang IV, Ang-(1e9), and Ang-(1e7). There are also various known receptors with stimulatory and inhibitory properties. Clinically important is the fact that active Ang II binds to AT2 receptors and Ang IV to AT4 receptors that are not antagonized by sartans inducing proinflammatory and profibrotic effects (e.g., induction of chemokines, stimulation of PAI-1). For details, see text.

activated protein kinase (AMPK) was identified as a kinase responsible for this phosphorylation of ACE2 adding to the complexity of regulatory mechanism [36]. In contrast to the “classic” ACE, which converts angiotensin I (Ang-(1e10), Ang I) to the octapeptide Ang II (Ang-(1e8)), ACE2 cleaves Ang I to generate Ang(1e9) peptide (Fig. 8.3). Furthermore, ACE2 metabolizes Ang II to generate Ang-(1e7). Ang-(1e7) evokes vasodepressor effects in conscious rats and augments bradykinin action on its B2 receptor by probably inducing conformational changes in the ACE/B2 receptor complex via interaction with ACE [37,38]. Part of the vasodilator actions of Ang-(1e7) are explained by Akt-dependent activation of endothelial nitric oxide synthase [39,40]. In a second step, Ang-(1e9) can be converted to Ang-(1e7) by the “classic” ACE. A major pathway of Ang-(1e7) degradation converting the peptide into inactive fragments is then further mediated by ACE. Among its vasodepressor effects, Ang-(1e7) is also involved in apoptosis, suppresses hypertrophy, and has antifibrotic and antiinflammatory properties [41]. The chronic exogenous administration of Ang-(1e7) or the more peptidase-resistant cyclic (c) Ang-(1e7) attenuated the progression of diabetic nephropathy in Akita and ob/ob diabetic mice [42e44]. Some of these mechanisms are mediated by Ang-(1e7)induced inhibition of the mitogen-activated kinase (MAP) pathways [45]. The protein product of the c-mas gene is a receptor for Ang-(1e7) (Fig. 8.3) [46]. Several

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years ago, when this relationship was not known, we found that overexpression of cmas in tubular cells attenuated the Ang II-mediated increase in transforming growth factor beta (TGF-b) expression [47]. Thus, our earlier findings could be explained by increased actions of Ang-(1e7) that counteract Ang II-mediated TGF-b expression. The expression of ACE2 correlates closely with the local concentration of Ang-(1e7) and leads to a partial antagonism of Ang II [48]. ACE2 has been shown to prevent the adverse effects of Ang II on the kidney: loss of ACE2 worsens Ang II-induced renal NADPH oxidase activation, inflammation, and tubulointerstitial fibrosis [49]. As a consequence, ACE inhibition can lead to increased Ang(1e7) concentrations while reducing Ang II in parallel [11]. Indeed, infusion of Ang II into ACE2-deficient mice induced a significant higher blood pressure associated with higher Ang II levels [50]. ACE2-deficient mice develop glomerulosclerosis and albuminuria at 12 months of age [51]. These changes were prevented by an Ang II receptor antagonist [51]. This observation suggests that deletion of the ACE2 gene causes glomerulosclerosis by shifting the pathways away from Ang-(1e7) formation toward unopposed Ang II production. In renal biopsies of patients with diabetic nephropathy, an increase in ACE2 immunostaining was detected, whereas in early experimental diabetes, ACE2 expression was suppressed [52,53]. The various effects of Ang II are mediated by a set of different receptors. The two major Ang II receptors, called AT1 and AT2, are differentially expressed within in the kidney (Fig. 8.3) [54]. Both receptors are characterized by a configuration of a seven-transmembrane receptor, but they share only around 30% homology on the protein level. Almost all Ang II-induced physiologic and pathophysiological functions (e.g., vasoconstriction, aldosterone release, stimulation of tubular transport, proinflammatory effects, and profibrogenetic and growth stimulatory actions), as depicted in Fig. 8.1, are mediated by AT1 receptors [55]. These receptors are coupled to heterotrimeric G proteins and have further downstream different, second messenger signal transduction pathways, including activation of phospholipases, inhibition of adenylate cyclase, stimulation of tyrosine phosphorylation, extracellular signal kinases 1/2 (Erk 1/2), the phosphatidylinositol 3-kinase (PI3K)-dependent kinases Akt, and the mTOR/S6 kinase pathway [55e57]. The traditionally described pathway of AT1 receptor signaling is activation of phospholipase C (PLC) and the later formation of diacylglycerol (DAG) and inositol trisphosphate, which subsequentially lead to an increase of protein kinase C activity and to an increase in levels of free intracellular calcium. AT1 receptors can form dimers [58,59]. Heterodimers between AT1-receptors and bradykinin receptor [58] as well as AT1 receptor homodimers [59] have been found. Homodimers are formed by covalent binding at the glutamine residue 315 of the intracellular domain and are detected on monocytes of patients with essential hypertension [59]. Apparently, AT1 receptor hetero- and homodimers exhibit an increase in signal transduction activity after stimulation with Ang II. The number of AT1 and AT2 receptors is developmentally regulated, and during maturation of the kidney, AT1 receptor expression becomes more abundant [55].

3. The renal renineangiotensin system

AT1 receptors are upregulated by different stimuli such as hypercholesteremia [60] and osmolar changes [61], but AT1 receptor expression is suppressed by high Ang II concentrations or glitazones [62,63]. N-acetylcysteine, an antioxidant reducing disulfide bonds, thereby decreases Ang II binding to AT1 receptors [64]. Accumulating evidence indicates that important downstream effects of AT1 receptors are independent of classical G protein coupling [57]. For example, AT1 receptoremediated endocytosis, tyrosine phosphorylation, and activation of protein kinases occur independent of G proteins [65]. Ang II-mediated phosphorylation of Smad1 is transduced through AT1 receptors involving Src [66]. A mechanism by which Ang II transactivates the epidermal growth factor receptor (EGFR) during renal injury has been described [67]. In addition, Ang II mediates secretion of transforming growth factor-alpha (TGF-a) that binds to and activates EGFR, explaining how Ang II through transactivation of the EGFR may stimulate tyrosine kinase activity [67]. Similarly, Ang II mediates the extracellular cleavage of proheparinbinding EGF (HB-EGF) by activation of matrix metalloproteases with liberation of soluble HB-EGF that could activate EGFR [68,69]. AT1 receptor activation also stimulates release reactive oxygen species (ROS) by a mechanism involving activation of the membrane-bound NAD(P)H-oxidase [70]. Ang II activates NAD(P)H oxidase by various mechanisms depending on the cell type. For example, in vascular cells, caveolin 1 (a component of caveolae/lipid rafts that are cholesterolenriched specialized membrane microdomains) is necessary for Ang II-mediated Rac1 and NAD(P)H oxidase activation and ROS generation [71]. Ang II upregulates various NAD(P)H oxidase subunits including Nox1, p47phox, p67phox, and p22phox through AT1 receptor activation [72e74]. Ang II infusion leads to blunted ROS formation and an attenuated blood pressure response in Nox1-deficient mice [75]. Additionally, Ang II facilitates assembly of NAD(P)H oxidase subunits. Ang II has been found to induce serine phosphorylation of p47phox resulting in an increased binding of p47phox to p22phox [76]. Ang II also stimulates Rac1 by disrupting the binding of Rac to the GDP dissociation inhibitor RhoGDI. Rac1 in turn binds to and activates Nox4, increasing ROS generation [77]. In contrast to AT1 receptor activation, it appears that Ang II-mediated stimulation of AT2 receptors downregulates several NAD(P)H oxidase components (Nox1, p22phox, p67phox) [78,79]. There is also evidence that Ang II-mediated transactivation of the EGFR may depend on ROS formation. Ang II-mediated liberation of H2O2 can lead to EGFR transactivation, where H2O2 acts upstream of the receptor. Furthermore, ROS induces the release of soluble heparin-binding EGF-like growth factor (HBEGF), which serves as signal to drive EGFR-dependent signaling pathways [80]. An AT1 receptoreassociated protein (ATRAP) has been isolated, which interacts specifically with the C-terminal cytoplasmic domain of the receptor [81]. In vitro studies showed that overexpression of ATRAP facilitates internalization of the AT1 receptor [81]. In the kidney, ATRAP is widely expressed in tubules and in glomeruli [82]. Dietary salt depletion significantly decreased the renal expression of ATRAP suggesting that the protein is a negative regulator of AT1 receptors by promoting endocytosis of receptors [82].

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The role of AT2 receptors is less clear. Stimulation of AT2 receptors leads to a decrease in blood pressure probably through release of nitric oxide and activation of cGMP-dependent pathways, inhibits growth and induces differentiation, and is also involved in mediation of apoptosis [55,83]. AT2 receptors are not suppressed by Ang II, but interestingly they are upregulated in inflammatorily modified and injured tissue [72]. In particular, AT2 receptors are reexpressed in the kidney during renal injury and remodeling nephrons [72]. AT2 receptor activation may, in addition to the well-known short negative feedback loop of the AT1 receptor to suppress renin, negatively influence renal renin production and can reduce blood pressure through this mechanism [84]. However, we found that activation of NF-kB, an important proinflammatory transcription factor, is mediated by AT1 and AT2 receptors [85]. Other studies have shown an antiinflammatory effect of AT2 receptor activation via suppression of mitogen kinaseedependent pathways [86]. Agonistic antibodies against AT1 receptors have been identified in pregnant women with preeclampsia and in patients with secondary malign hypertension [87]. These autoantibodies against AT1 receptors lead to a stimulation of the receptor (a similar mechanism such as activation of the TSH receptor in Grave’s disease) [62]. Certain renal transplant patients with chronic allograft rejection without classic HLA antibodies have such agonistic antibodies against the AT1 receptor, and these autoantibodies were involved in vasculitis with destruction of the renal allograft [88]. Ang II itself is further metabolized by enzymes, such as aminopeptidase A (APA) and aminopeptidase M (APM), into angiotensin III (Ang-(2e8)) and finally further into angiotensin IV (Ang-(3e8)) (Fig. 8.3) [89]. Whereas within the kidney Ang III is the predominant endogenous agonist for AT2 receptor [90,91], Ang IV interacts with AT1 receptor and binds to a specific receptor named AT4, which is identical with the enzyme insulin-regulated membrane aminopeptidase (IRAP) [92e94]. The AT4 receptor is expressed on several renal cell types including endothelial cells, and proximal and convoluted tubules [47,48]. AT4 receptor ligands such as Ang IV inhibit IRAP catalytic activity [92,95]. Ang IV stimulates plasminogen activator inhibitor-1 (PAI-1) expression in proximal tubular and endothelial cells through AT4 receptors [96]. Since PAI-1 reduces extracellular matrix turnover, Ang IV may induce renal fibrosis independently of activation of AT1 and AT2 receptors. Ang IV also activates the nuclear factor-kB pathways and stimulates transcription of proinflammatory genes through binding to the AT4 receptor [97]. The close association of the AT4 receptor/IRAP with the inducible glucose transporter GLUT4 suggests that Ang IV (and presumably other AT4 receptor ligands) may modulate glucose uptake into cells [98]. We have previously reported that Ang IVgenerating enzymes, such as APA, are upregulated in conditions with high Ang II and renal injury, such as diabetic nephropathy and renal ablation, likely shifting more Ang II into the degradation pathway to Ang IV [99e101]. We found that overexpression of APA in mouse mesangial cells attenuated the proliferative effects of Ang II, suggesting that Ang IV does not modulate growth in these cells, in contrast to findings in endothelial and vascular smooth muscle cells [102].

3. The renal renineangiotensin system

Two receptors that bind mature renin and prorenin have been identified (Fig. 8.3) [103,104]. One, the mannose-6-phosphate receptor (M6P-R), is a clearance receptor and is involved in internalization of prorenin/renin without apparent signal transduction activation [103]. The second prorenin/renin receptor (PRR) is a unique 350 amino acid transmembrane protein that binds prorenin and renin with similar affinity [105]. Binding of (pro)renin to this receptor provoked a rapid activation of MAP kinases (Erk 1/2) and stimulation of profibrotic molecules [106]. Furthermore, overexpression of PRR in smooth muscle cells of transgenic rats induced high blood pressure [107]. Thus, activation of the novel receptor by prorenin/renin induces direct pathophysiological changes independent of the generation of angiotensin fragments [65]. There are renin inhibitors such as aliskiren on the market or in development that inhibit the enzymatic activity of renin and abolish angiotensin I generation [108]. These substances are not direct PRR antagonists, but they can alter the structure of renin [108]. Although initial clinical studies revealed that aliskiren lowers proteinuria in patients with diabetes, longer follow-up observations demonstrated rather a deterioration of renal function in the long-term run [109]. This may be presumably caused by a compensatory upregulation of renin and angiotensinogen [109]. Therefore, aliskiren is no longer recommended as a primary substance to interfere with the RAS [109]. Nevertheless, this substance exhibits clear antioxidative properties inhibiting the formation of ROS [110]. Further clinical studies are necessary to find out whether this interesting effects could be useful under certain clinical circumstances. Polymorphisms for different components of the RAS such as ACE, angiotensinogen, or AT1 receptors have been described with controversial results [111], mainly explained by the different ethnic backgrounds of the study populations. In a large caseecontrol study with more than 1000 patients, it was shown that ACE polymorphisms (haplotype defined by the D, rs4366_G, and rs12449782_G alleles) were associated with diabetic nephropathy, but the association could not be confirmed in a family-based association study [112]. Experimental overexpression of three copies of the ACE gene leads to aggravation of diabetic nephropathy in mice in comparison with reduced ACE gene expression [113]. Thus, there is likely some genetic influence on the activity of the RAS, but how this translates into the individual risk of predisposition or progression of renal disease remains unclear.

3.1 Ang II and renal growth The growth-stimulatory effects of Ang II in the kidney have been known for about 30 years, and there are quite a few review articles available on this topic, especially regarding tubular hypertrophy [114e119]. Already in the early 1990s, we described Ang II’s properties as a renal hypertrophic and mitogen growth factor [117,118,120e125]. Beginning with the observation that ACE inhibitors, even in the absence of hemodynamic changes, can abolish compensatory renal enlargement to the in vitro growth effects of Ang II on various renal cell types [126]. Ang II exhibits distinct growth stimulatory effects depending on renal cell type:

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it induces (1) mild proliferation as well as hypertrophy in mesangial cells, (2) proliferation in glomerular endothelial cells, (3) strong proliferation in medullary thick ascending limb and interstitial fibroblasts, and (4) cellular hypertrophy without mitogenesis in proximal tubule cells [117,120,126,127]. The hypertrophy of proximal tubular cells is characterized by an increase in cell size, new protein synthesis, and the secretion of new basement membrane type IV collagen in the absence of cellular proliferation [123]. It has been shown that the transcription and secretion of type IV collagen is induced by Ang II and that the changes in tubular cells leading to secretion of collagen IV are mediated by a decrease in intracellular cAMP [128]. Furthermore, the hypertrophogenic effects of Ang II on proximal tubular cells partly depend on the increase in synthesis and/or activation of endogenous TGF-b1 by Ang II [124]. Using neutralizing monoclonal anti-TGFb antibody, we have demonstrated that also the Ang II-mediated stimulation of collagen type IV depends on the endogenous production of TGF-b1 [129]. We were able to clarify the mechanism of the Ang II-induced hypertrophy of proximal tubular cells in great detail, which is that Ang II enhances the cyclin-dependent kinase inhibitor, which in turn clamps cells in the G1 phase of the cell cycle [130]. The increased expression of p27Kip1 and induction of cellular hypertrophy are at the end of a signal transduction cascade starting from Ang II-mediated AT1 receptor stimulation, via an increase in NAD(P)H oxidase activity, the generation of oxygen radicals, and phosphorylation of Erk 1,2 [131,132]. Induction of p27Kip1 in renal cells and consequent inhibition of G1-phase CDK/cyclin complexes with G1 phase arrest do not occur exclusively via generation of oxygen radicals [133]. Exogenous TGF-b also stimulated p27Kip1 expression and arrested renal tubular epithelial cells in the late G1 phase, indicating that Ang II-stimulated hypertrophy and induction of p27Kip1 are partly mediated by TGF-b [130,133,134]. Furthermore, cellular hypertrophy in cultured mesangial cells has been shown to be induced by high-glucose medium via activation of protein kinase C (PKC) or stimulation of TGF-b1 [133,135]. EGFR activation also appears to play a major role in Ang II-induced cellular hypertrophy in renal epithelial cells expressing the AT1 receptor [80]. Here, transactivation of EGFR occurs through release of soluble HBEGF: after activation of AT1 receptor, a metalloproteinase is activated, which cleaves the membrane-bound proHB-EGF; then the soluble HB-EGF serves as a positive signal to drive protein synthesis and cell growth through activation of EGFR-dependent mTOR signaling pathways [80]. In addition to its pathophysiological role as a growth factor, Ang II’s role as an important factor in the structured growth events of renal organogenesis is also well known [136e138]. AT1, not AT2, receptor blockade decreased renal growth, altered renal architecture markedly, induced extensive vascular abnormalities, and marked tubular dilatation [136]. Moreover, AT1-selective angiotensin II receptor antagonist losartan showed developmental toxicity in rats [138], and at the latest, since some cases became known about fatal fetal toxic effects after maternal exposure to this antihypertensive drug during pregnancy in human, it was clear that Ang II receptor blockers are contraindicated with pregnancy [139,140].

3. The renal renineangiotensin system

3.2 Ang II and renal inflammation Inflammation is considered to be an important precursor and key driver of fibrosis. Kidneys of the unilateral ureteral obstruction (UUO), a widely used mouse model of renal fibrosis, showed significant increase in infiltration of a multitude of different immune cells, such as CD3þ T cells, effector and regulator T cells, cytotoxic T cells, natural killer cells, gamma delta T cells, dendritic cells, B cells, and macrophages [141]. Initiated as a protective response to injury, the immune infiltrate evolves and differentially regulates organ fibrosis [128]. It is known that diverse bioactive components of the RAS have multiple pleiotropic actions that contribute to tissue injury, including modulation of inflammation [142]. In the earlier literature, one can find mostly data regarding the inflammatory actions of Ang II, Ang-(1e7), and aldosterone. The classic view of RAS is that Ang II induces endothelin-1, platelet-activating factor as well as various chemokines (e.g., monocyte chemoattractant protein-1 [MCP-1)] interleukin 8), cytokines (e.g., interleukin 6, TNF-a), and adhesion molecules in renal cells [142e146]. Ang II exerts its proinflammatory effects in the kidney through an AT1Rmediated activation of nuclear translocation of transcription factor NF-kB [85]. Using cultured glomerular endothelial cells isolated from rats, we could also demonstrate that Ang II exerts its immunomodulatory properties in the kidney also through the induction of RANTES via AT2 receptors [147]. RANTES is a member of the CC-chemokine subfamily and is chemotactic for macrophages/monocytes, eosinophil and basophil granulocytes, and T lymphocytes [147,148]. In addition, the tubular overload of plasma proteins with increased glomerular permeability by Ang II stimulates proximal tubular cells to synthesize and release MCP-1 and RANTES [149]. Furthermore, in vitro as well as in vivo data suggest that Ang II leads to an upregulation of Toll-like receptors (TLRs), e.g., TLR4 in mesangial cells [142,150]. The stimulation of TLR4 mRNA transcription was shown to be via activation of AP-1 (activating protein 1) and Ets (E-26 specific sequence)-dependent TLR4 promotor activity [150]. The Ang II-mediated upregulation of TLR4 results in enhanced NF-kB signaling and induction of chemokines and triggers further inflammation in the kidney [150]. We further found in in vitro experiments that Ang II differential regulates the TLR4 expression in mouse renal cell types: Ang II stimulated TLR4 mRNA and protein in mesangial cells, podocytes but not in proximal tubular cells [151]. As mesangial cells, podocytes, and proximal tubular cells similarly express Ang II receptors, the differences in Ang II-induced TLR4 expression are probably caused by cell typeespecific transcriptional activation of the TLR4 gene [151]. The knowledge to RAS-TLR cross-talk is still in the fledgling stages. There is evidence that the TLR4 coreceptor myeloid differentiation factor 2 (MD2) is required for local kidney RAS activation and inflammation in diabetic mice and that MD2 mediates Ang II-induced kidney inflammation by directly binding to Ang II [152,153]. There are recent advances in the understanding of RASeinflammation interaction with more focus on RAS suppression of antiinflammatory factors [142]. RAS

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downregulates antiinflammatory factors through mechanisms dependent on epigenetic regulators, transcription factors, and posttranslational modifications of proteins and peptides (reviewed in Ref. [142]). A central role plays the interaction between RAS and klotho: there is a bidirectional relationship by which Ang II decreases klotho expression and klotho decreases the expression of angiotensinogen, renin, ACE, and AT1 receptor [142].

3.3 Ang II and renal fibrosis Fibrosis is the final result of chronic inflammation and part of the normal repair process that is triggered in response to injury [128,154]. Kidney fibrosis is characterized by accumulation of extracellular matrix proteins in the glomerulus and tubulointerstitium. Glomerulosclerosis and tubulointerstitial fibrosis occur in progressive kidney disease as well as in aging kidneys. In addition to this pathohistological similarity between the aging kidney and chronic kidney disease, there are also similar underlying mechanisms, such as oxidative stress, inflammation, and activation of the RAS [155]. Both injured tubules and inflammatory cells can stimulate interstitial fibroblasts to collagen-producing myofibroblasts, which are the key cellular mediators of fibrosis [149]. Myofibroblasts are generated from a variety of sources including epithelial cells in a process termed epithelial-to-mesenchymal transition (EMT). Moreover, myofibroblasts are activated by a several mechanisms, including paracrine signals derived from lymphocytes and macrophages [128]. More than 30 years ago, the landmark study by Border et al. first drew attention to the role of TGF-b1 in fibrotic kidney disease [156]. Only a few years later, Ang II was shown to induce TGF-b1 in proximal tubule cells as well as in glomerular mesangial cells, thereby contributing to the development of fibrosis [124,157]. Shortly thereafter, an Ang II-induced upregulation of TGF-b1 receptor type II expression was shown in mouse proximal tubular cells [158]. Since these initial findings, there have been countless studies on the role of Ang II in renal fibrogenesis. Now, a PubMed search using the keywords ‘angiotensin II’ and ‘renal fibrosis” yields almost 1500 hits, of which 300 have appeared in the past 5 years and more than 60 since 2021. Fig. 8.4 provides a general overview of the role of Ang II as a cytokine-stimulating renal fibrogenesis. It is known that Ang II stimulates the synthesis of extracellular matrix proteins, e.g., increases the biosynthesis of type I collagen in mesangial cells and type IV collagen in proximal tubular cells [129,159]. There is a cross-talk between Ang II and TGF-b in renal fibrosis: Ang II via AT1 receptor directly upregulates TGF-b expression, and the Smad and non-Smad-dependent signaling contribute to the transcription of TGF-b1 target genes (Fig. 8.4) [124,129,149]. Mechanical strain, as a result of glomerular capillary hypertension, both increases TGF-b expression and activates local tissue angiotensin system (AT1 receptor and Ang II) in podocytes [160]. There also appears to be a link between Ang II and the toxic effects of proteinuria on tubular cells [161]. Proteinuria is a common finding in many renal

3. The renal renineangiotensin system

FIGURE 8.4 Cells, mediators, and mechanisms involved in Ang II-induced renal fibrosis. Ang II exerts its effects on inflammatory cells and the various renal cells via different receptors. Activation of the AT1R by Ang II increases a variety of bioactive substances such as profibrotic and growth factors, extracellular matrix components, and cytokines. Although the Ang II/AT1 receptor axis is the classical one through which most effects are induced, there are other important axes of RAS: for example, the angiotensin II/ACE2/angiotensin (1e7)/MAS receptor axis, which acts to oppose the harmful effects of Ang II. ACE2, angiotensin-converting enzyme 2; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II type 2 receptor; COX-2, cyclooxygenase 2; CTGF, connective tissue growth factor; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; EMT, epithelial-to-mesenchymal transition; ET-1, endothelin-1; IL-6, interleukin 6; IL-8, interleukin 8; MAS R, MAS1 oncogene receptor; MCP-1, monocyte chemoattractant protein-1; PAI-1, plasminogen activator inhibitor-1; PCNA, proliferating cell nuclear antigen; PDGF, platelet-derived growth factor; RANTES, regulated and normal T cell expressed and secreted; ROS, reactive oxygen species; TGF-b1, transforming growth factor beta 1; TGFBR, transforming growth factor beta receptor; TIMP1, tissue inhibitor of matrix metalloproteinases; TNF-a, tumor necrosis factor alpha.

diseases and is closely involved in proinflammatory and profibrotic changes of the tubulointerstitium [162]. We found that albumin, one of the major components found in proteinuria, upregulates TGFBR-II on proximal tubular cells and that the albumin-induced activation of local Ang II production appears to be responsible for this effect [161]. It has been demonstrated that in renal mesangial and tubular epithelial cells, Ang II activates plasminogen activator inhibitor-1 (PAI-1) promotor and upregulates its production [163,164]. This Ang II-induced PAI-1 expression is mediated by TGFb1 [149]. TGF-b1 also triggers ROS that activates EGFR signaling and p53, which in turn interacts with Smads and transcriptional cofactors forming transcriptionally

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active multiprotein complexes important for maximal PAI-1 induction [165]. The biological role of PAI-1 is to inhibit plasmin-mediated ECM degradation leading to ECM stabilization/accumulation [149]. The TGF-b1/Smad/p53/PAI-1 transcriptional axis contributes to renal fibrosis in UUO and in diabetic nephropathy [149,166]. In addition to the role of EGFR in cellular hypertrophy/growth and overproduction of inflammation factors, EGFR transactivation by Ang II and AT1R interaction also plays a vital role in kidney fibrosis (Fig. 8.4) [67,167]. Novel analogs of AG1478, the classic EGFR inhibitor, which block EGF-EGFR interaction, were used to determine the effects of EGFR inhibition on ANG II-induced renal fibrosis and the underlying mechanism [167,168]. The inhibitors 451 and 557 attenuate Ang II-induced increase in profibrotic proteins (CTGF, TGF-b1), and collagen IV in renal cells and the 557 analog suppress Ang II-induced EGFR signaling pathways (via pAKT and p-ERK) and fibrosis in vivo [167]. In another study, the AG1478 analog 453 was used to investigate the effect of EGFR inhibition in mice treated with Ang-II [168]. 453 inhibited EGFR and its downstream signaling pathways (AKT and ERK) and prevented the activation of fibrotic (collagen, CFGF, TGF-b1), inflammatory (COX2, IL-6, IL-1 beta, TNF-alpha), apoptosis, and oxidative stress pathways [168]. Many profibrotic effects of Ang II causing apoptosis or tubular EMT are dependent on AT1 receptor stimulation that leads not only to increased TGF-b1 but also to ROS production by NAD(P)H oxidase (Fig. 8.4) [149,169]. One mechanism by which ROS mediates Ang II-induced renal interstitial fibrosis is via hypoxiainducible factor 1a (HIF-1a) [149,170,171]. Ang II stimulates generation of ROS that increase HIF-1a translation and inactive prolyl hydroxylase (PHD)edependent proteasomal degradation of HIF promoting its stabilization. HIF-1a forms with the b-subunit an active heterodimer that translocates into the nucleus and induces the transcription of profibrotic markers collagen I/III, tissue inhibitor of metalloproteinase (TIMP-1), proliferating nuclear antigen (PCNA), and vimentin [149]. It has been shown that PHD2 is necessary for Ang II-induced renal fibrosis: knockout of PHD2 significantly reduced the expression of AT1 receptor and blunted Ang IImediated renal fibrosis [172]. In these PHD2 knockout mice, the Ang II-induced NADPH oxidase expression and ROS formation were significantly reduced in both renal cortex and medulla [172]. An increasing number of studies revealed that microRNAs (miRNAs/miRs) may be closely associated with renal interstitial fibrosis. For example, it has been reported that Ang II, TGF-b1, and hypoxia increase the expression of miR-212 and that in UUO mice, miR-212 overexpression promoted the progression of renal interstitial fibrosis [173]. Furthermore, the study showed that miR-212 targets and negatively regulates HIF-1a inhibitor and upregulates HIF-1a [173]. Recent studies link fibrosis to changes in miRNA modulated by ANG II through Smad3-dependent TGF-b1 signaling [149]. For example, in vitro analyses using NRK-52E cells (a rat renal tubule epithelial cell line) suggest that the antifibrotic effects of miR-29b in the obstructed mouse kidney with UUO are due to inhibition of Ang II-induced EMT [174]. In 2011, Burns et al. have demonstrated the role of Ang

3. The renal renineangiotensin system

II in tubular EMT associated with chronic kidney disease [175]. Data from in vitro as well as in vivo experiments showed that Ang II is able to induce EMT by both TGFdependent and TGF-independent actions [175]. Recently, a mechanism explaining the renoprotective effect of losartan, the AT1R antagonist, was revealed: Losartan reversed the EMT-like changes in proximal tubular cells from spontaneously hypertensive rats, and this EMT-negative regulation is mediated by heat shock protein 70 kDa (Hsp70) [169,176]. A study of Zhang et al. provides novel insights into precise molecular mechanism by which miR-29b-3p is negatively regulated in response to fibrotic stimuli [177]. The modulation is mediated by direct binding of mineralocorticoid receptor (MR) to long noncoding RNA Tug1 [177]. The identification of MR-Tug1-miR-29b-3p axis is an important step toward understanding Ang IIinduced renal fibrosis. The excessive deposition of extracellular matrix proteins in the glomerulus and in the renal tubulointerstitium is typical hallmark of diabetic nephropathy, one of the most serious complications in diabetic patients and the leading cause of end-stage renal disease worldwide [178]. In rats with STZ-induced diabetic nephropathy (a model of type 1 diabetes mellitus), intrarenal RAS was shown to be activated in early phase. Compared with the healthy control group, intrarenal protein expression of ACE, Ang II, and AT1 receptor was significantly increased in the diabetes group, whereas measurement of circulating RAS (plasma renin activity PRA and Ang I) showed no differences [179]. Treatment of type 2 diabetic db/db mice with losartan (an AT1R blocker) reversed key parameters of renal dysfunction and inhibits glomerular expression of inflammatory and extracellular matrix genes (RAGE, MCP-1, and PAI-1) [180]. Moreover, the renoprotective effect of losartan in db/db mice could be partly attributed to the reversal of diabetic nephropathy-related RNA polymerase II recruitment at PAI-1 and RAGE gene promotors and permissive, not repressive, histone posttranslational modifications [180]. Aforesaid, PRR is known to be a positive regulator of intrarenal RAS. Although PRR is predominantly expressed in the intercalated cells of the collecting duct, an activation of PRR in various other renal cells (such as mesangial cells, podocytes, and proximal tubule cells) seems to be implicated in the pathophysiology of diabetic nephropathy [181,182]. However, it is still not entirely clear by which mechanism PRR contributes to TIF. Renin increases profibrotic molecules, such as PAI-1 and TGF-b1, through PRR in mesangial cells [106]. Recent work shows that hyperglycemia in a rodent model induces a specific, namely apical, localization of PRR in the collecting duct (in collecting duct, the principal cell is the main source of prorenin in diabetes) [181]. Furthermore, they demonstrated that the glucose-induced PRR translocation to the apical cell side of collecting duct cells induces the physical interaction of prorenin and PRR. The subsequent signaling via Erk 1/2 leads to upregulation of fibrotic (TGF-b1, fibronectin, and collagen I) and possibly inflammatory cytokines [181]. To the complex regulatory networks, which control the local RAS, belong also the PGE2/EP4 pathway and Wnt/b-catenin signaling as positive regulators: PGE2/ EP4 pathway independently stimulate PRR and renin in the distal nephron, and there

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appears to be a mutually stimulatory relationship between Ang II and Wnt/b-catenin signaling during renal fibrosis [183]. The intrarenal RAS is not only positively regulated but also under control of negative regulators, such as liver X receptor, vitamin D receptor, and klotho [183]. As mentioned before, there is an interaction between RAS components and klotho, which has consequences not only for inflammation but also for fibrosis. Klotho is already downregulated in chronic kidney disease category G1, when glomerular filtration rate is still normal: albuminuria directly suppresses the production of klotho by renal tubular cells, which are the main source of the antiaging factor [184]. In mouse models of remnant kidney, as well as adriamycin and obstructive nephropathy, exogenous klotho gene delivery ameliorated renal fibrotic lesions [185]. In cardiac fibrosis, the inhibition of Ang II-mediated effects by klotho is through suppression of TGF-b1 signaling [186]. As mentioned before, Ang-(1e7) and ACE2 prevent the adverse effects of Ang II on the kidney, namely renal NAD(P)H oxidase activation, inflammation, and tubulointerstitial fibrosis (Fig. 8.4) [42e44,49]. ACE2 knockout kidneys in response to Ang II showed greater elevation in the mRNA expression of a-smooth muscle actin, TGF-b1, procollagen type Ia1, and collagen I compared with wild-type mice treated with Ang II [49]. Whereas the Ang II degradation pathways that involve ACE2 are found abundantly in kidney tubules and in lesser amounts in podocytes, the glomerular expression of APA is high, suggesting that APA is the dominant Ang II degrading enzyme in the glomerulus [187,188]. Knockout of APA in mice causes mild glomerular mesangial expansion by increase of mesangial matrix. Furthermore, these mice exhibit moderate thickening of glomerular basement membrane and a strike appearance of knob-like structures, suggesting an important role for APA in the maintenance of glomerular structure by controlling the homeostasis of Ang peptides [188]. In recent years, more and more findings have come to light, which contributes to a better understanding, but at the same time increases the complexity: Proinflammatory cytokines, such as IL-1b and IL-6, increase as hypertension becomes more severe, but the precise mechanism by which inflammation leads to renal injury is poorly understood [189]. IL-1 receptor agonist (IL-1Ra) negatively regulates the signaling of IL-1 and plays an antiinflammatory role in acute and chronic inflammation [190]. A recent study demonstrated that IL-1Ra deficiency deteriorated renal function and promoted tubulointerstitial fibrosis in Ang II-infused mice [189]. Regarding Ang II-induced kidney inflammation, the local RAS activation is mediated by directly binding of Ang II to MD2, the accessory protein of TLR4. This seems to be the case not only for proinflammatory effects of Ang II, but also the Ang II-induced profibrotic responses in renal tubular cells is MD2-dependent [191]. Pretreatment with L6H21, an MD2 inhibitor, prevents Ang II-induced mRNA and protein expression of TGF-b1, collagens I and IV, CTGF, and MMP9 in a dose-dependent manner [191]. The molecular mechanism of Kru¨ppel-like factor 15 (KLF15), a transcriptional regulator with a wide range of functions, in the regulation of TGF-b-induced renal

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4. Conclusion and future directions Knowledge of the underlying mechanisms by which Ang II contributes to renal fibrosis is increasing. The effects of Ang II on cell growth and inflammation in kidneys also play a role in fibrosis. Although it is undisputed that the angiotensin I/ACE/angiotensin II/AT1 receptor axis is the major axis in the pathophysiology of RAS in the kidney, other proinflammatory/profibrotic pathways, mediated by different receptors, are induced by Ang II. In recent years, however, deeper insights have also been gained into negative regulators of RAS, i.e., those that counteract the harmful Ang II effects. Taken together, this increases the possibilities for novel therapeutic targets. A very recent review of the main clinical trials addressing RAS to delay progression of chronic kidney disease, however, dampens expectations a bit: The authors conclude that to date, although several clinical trials showed some positive results, therapeutic interventions when tubulointerstitial fibrosis is already established have proved to be insufficient [154]. This means that further research is still needed for an even better understanding of the molecular basis for integrative control of intrarenal RAS to open up new perspectives for the therapy of kidney diseases and especially renal fibrosis.

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Further reading [1] Kelly JG, O’Malley K. Clinical pharmacokinetics of the newer ACE inhibitors. A review. Clin Pharmacokinet 1990;19:177e96.

CHAPTER

Angiotensin and atherosclerotic vascular disease

9

¸ alaru1, 2, Cristina Adam1, Drago¸s Traian Marcu2, Radu Andy Sasc
au1,2, Delia Lidia S Cristian St
atescu1, 2 1

Institute of Cardiovascular Diseases Prof. Dr. George I.M.Georgescu, Iasi, Romania; 2University of Medicine and Pharmacy Grigore T.Popa, Iasi, Romania

1. The global burden of the atherosclerotic vascular disease Cardiovascular disease (CVD) is a global burden for both social and medical systems. In high-income countries, CVD are the leading cause of mortality and morbidity, being estimated on the basis of prevalence to become the major cause of death [1,2]. The occurrence of CVD at younger ages influences the socioeconomic balance despite therapeutic advances of both interventional therapeutic procedures and newly discovered drugs [3,4]. Atherosclerosis is a multifactorial process, in which genetic and environmental factors are involved [5]. Traditional cardiovascular risk factors such as smoking, hypertension, diabetes, obesity, and high cholesterol levelsdalthough useful in population studiesdfail to explain the variable nature of disease progression and interindividually different clinical presentations. Genetic polymorphisms of the enzymes responsible for endothelial cell function and for thrombotic factors may cause variability in clinical signs [6,7]. Genetic determinants of lipid metabolism, variations of coagulation factors, and fibrinogen lead to increased thrombogenicity. Coronary artery disease and hypertension have an increased risk of occurrence in patients with mutations of factors involved in renineangiotensin pathway and certain variants of endothelial nitric oxide (NO) synthase [5,8]. Atherosclerosis is a chronic inflammatory disease of the large- and mediumsized arteries characterized by endothelial dysfunction and subsequent plaque formation in the vascular wall (Fig. 9.1). Atherosclerotic manifestations in the distal aorta and arteries of the lower limbs are termed peripheral arterial disease and affect 3%e10% of the population younger than 70 years and 15%e20% of the population over 70 years. Although several important cytokines orchestrating inflammatory processes are expressed in atherosclerotic lesions in humans, further research is necessary to establish their involvement in the various manifestations of this disease and their role in counterregulatory neoangiogenesis that might ameliorate peripheral ischemia. Angiotensin. https://doi.org/10.1016/B978-0-323-99618-1.00032-5 Copyright © 2023 Elsevier Inc. All rights reserved.

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FIGURE 9.1 Schematic design of the central elements involved in atherosclerosis: oxidized low-density lipoprotein (oxLDL), injury of endothelial cells, inflammation, and increased platelet aggre gation.

2. Endothelial dysfunction The vascular endothelium plays an essential role in the development and progression of atherosclerosis. Endothelium dysfunction underlies the cardiovascular continuum, so that deepening the molecular mechanisms underlying it might be the key to interrupting the pathophysiological processes that lead to hypertension, atherosclerosis, coronary artery disease, or heart failure [9]. Due to its role as a barrier between the blood and the vascular wall, it can be considered as a multifunctional endocrine organ with several strategical roles such as regulation of vascular tone, synthesis of NO and prostacyclins, coagulation, fibrinolysis, adhesion, and migration of blood cells [10,11]. Its activity is influenced by multiple factors such as hormones, neurotransmitters, or vasoactive factors such as acetylcholine or bradykinin [12,13]. Turbulent blood circulation and stretching of blood vessels are predisposing factors for the early development of atherosclerosis. These factors associated with the presence of reactive oxygen species (ROS) encountered in the presence of smoking, anaerobic metabolism, and radiation lead to worsening of endothelial dysfunction. The activation of endothelial cells causes secretion of vasoconstrictor substances that influence the differentiation and maturation of vascular smooth muscle cells [5,14,15]. Different studies conducted so far have shown that the overexpression

3. The renineangiotensin system

FIGURE 9.2 Components of the endothelial dysfunction.

of cellular adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, P selectin) on the surface of macrophages and endothelial cells stimulates the appearance and progression of the atherosclerotic process. Proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF)-a are associated with leukocyte adhesion and activation, which secondly determines endothelial dysfunction and injury by producing ROS (Fig. 9.2). Many cardiovascular drugs have effects on the endothelium, as in the case of angiotensin-converting enzyme (ACE) inhibitors, which are widely used in the treatment of CVD having a demonstrated effect in both primary and secondary prevention of atherosclerosis. Besides their role in reducing the blood pressure, they also have an antiinflammatory activity, which improves the endothelial dysfunction [13,16]. Endothelial dysfunction of small resistance vessels occurs before the involvement of large vessels [17e19]. The migration of vascular smooth muscle cells into intima can be interpreted as the starting point of neointima formation [20,21].

3. The renineangiotensin system The renineangiotensin system (RAS) is a hormonal system with various effects on blood pressure, electrolyte balance, and blood flow. Its activation in the heart and blood vessels both amplifies and supports its role in the development and progression of atherosclerotic lesions [13,22]. RAS blockade exerts important antiatherosclerotic effects, not only through the antihypertensive pathway but also through

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FIGURE 9.3 Angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptor (AT2R) implications in the atherosclerotic process.

antiinflammatory, antiproliferative, and antioxidant properties [23]. Both local and circulating angiotensin II carry out their activities by binding to angiotensin type 1 (AT1) or type 2 (AT2) receptors. The AT1 receptor (AT1R) is widely expressed on a variety of cell types involved in atherogenesis. AT1R activation not only causes vasoconstriction, induction of inflammatory, fibrotic, and thrombotic processes but also increases production of reactive oxygen species in the vasculature, which may ultimately result in disturbance of endothelium-dependent vasodilation. Heart failure, diabetes mellitus, hypertension, or peripheral artery disease are known to associate an AT1R upregulation [24]. AT2 receptors are predominantly found in several tissues including the adrenal gland, heart, or brain, and through activation determine vasodilation and natriuresis [25,26]. Most of the effects of angiotensin II (Ang II) are exerted via AT1 receptors, in particular vasoconstriction. The effect on AT2 receptors is the opposite, vasodilation, through mechanisms mediated by nitric oxide in a bradykinin-dependent or independent manner (Fig. 9.3) [27,28]. Endothelial cells increase bradykinin production and NO synthase activity via AT2R-mediated signaling pathways [29].

4. The role of angiotensin in the pathophysiology of atherosclerotic plaques Angiotensin is the main component of the RAS and is known as a peptide involved in multiple pathophysiological processes in atherosclerotic plaques such as regulation of vascular hypertrophy and hyperplasia, vascular cell migration, and expression of proinflammatory genes [30] (Fig. 9.4). In addition to its known hypotensive effect, Ang II also acts as a cellular growth factor. Up until now, several studies have demonstrated that Ang II activates several nuclear transcription factors such as nuclear factor kappa B (NF-kB), STAT (signal transducer and activator transcription factor), AP-1 (activator protein-1), and CREB (cyclic AMP response elementebinding protein). NF-kB plays an essential role in the regulation of molecules involved in the vascular injury such as cytokines, chemokines, adhesion molecules, and angiotensin [31]. The

4. The role of angiotensin in the pathophysiology of atherosclerotic

FIGURE 9.4 Angiotensin II actions in the atherosclerotic process.

beneficial role of AT1R antagonists was demonstrated first, leaving the question of the potential effect of antagonists on AT2R. Wolf et al. used rat glomerular endothelial cells that express AT1 and AT2 receptors and PC12 cells that exclusively exhibit AT2 receptors to study the effect of NF-kB activation in Ang II-mediated inflammation. By confirming the AT2R expression by Western blots of membrane lysates, they concluded that the inhibition of AT2R may have therapeutic implications as the strict use of AT1R antagonists does not abolish the proinflammatory effect caused by Ang II [31,32]. Consistently with the previous study, Ruiz-Ortega et al. investigated the connection between Ang II and NF-kB, concluding that via AT1 and AT2, Ang II activates NF-kB in vitro and in vivo the vascular cells. This effect was diminished secondary to administration of AT1 (losartan) and AT2 antagonists. Besides activation of NF-kB, Ang II increases the expression of IL-6, MPC-1, and TNFa in monocytes in human vascular smooth muscle cells [20,33,34]. In addition to activating molecules, Ang II intervenes in the atherosclerotic process as a secondary messenger by activating intracellular signaling pathways with a role in maintaining endothelial dysfunction, such as mitogen-activated protein kinase (MAPK) and AKT [35]. In addition to Ang II, other peptides of the same category are involved in the atherosclerotic process such as Ang peptides Ang III (Ang-2e8), Ang IV (Ang 3e8), and Ang 1e7. Of these, one of the most studied is Ang 1e7, which has a vasodilating action and modulates the antiangiogenic and antimitogenic processes [36]. Ang 1e7 exercises its positive cardiovascular effects via G proteinecoupled receptor Mas (MasR) [37,38] found in endothelial cells, afferent arterioles, and renal structures. Previous studies demonstrated that Ang 1e7 inhibits neointima formation following carotid injury or abdominal aorta stenting [38]. Synthesis of this molecule occurs predominantly in the endothelium, which explains its interaction with other vasodilator molecules such as NO.

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Davie and McMurray conducted a study in which eight patients with heart failure due to left ventricular systolic dysfunction treated with ACE inhibitors were enrolled and in whom intravenous administration of bradykinin and Ang 1e7 was performed. Local infusion of bradykinin and Ang 1e7 did not result in a systemic vasodilator response [39]. However, Ang 1e7 acts as a partial mediator, its plasma levels being influenced by the administration of ACE inhibitors. Santos et al. concluded that plasma levels of Ang 1e7 increase during treatment with ACE inhibitors or ARB. The expression of MasR seems to be independent to the effect of Ang II and aldosterone in hypertensive patients, suggesting therefore the existence of an RAASindependent signaling pathway underlying the development of new therapeutic molecules [36,40]. Zhang et al. demonstrated that Ang 1e7 effects antagonize those of Ang II in terms of proliferation of the vascular smooth muscle cells, migration, or inflammation by activating MasR and suppressing the ROS-dependent PI3K/Akt and MAPK/ ERK signaling pathway [20]. Macrophages have a high content of angiotensin-converting enzyme, both those from uncomplicated atherosclerotic lesions or from ruptured lesions [41]. Ohishi et al. studied the connection between angiotensin-converting enzyme and the development of coronary atherosclerosis, concluding that the progression of atherosclerosis is deeply connected to the histologic characteristics of plaques. Immunocytochemical tests were performed on 44 coronary artery segments from 19 patients who died of acute myocardial infarction. ACE was expressed in the endothelial cells of normal arteries with diffuse intimal thickening and in macrophages and smooth muscle cells of hypercellular lesions and atheromatous plaques. Although ruptured plaques have been associated with high levels of ACE in macrophages of the fibrous cap, the level of ACE in the fibrosclerotic plaques was extremely low [42,43]. The expression of different components of RAS has been extensively studied in human coronary arteries, but the information regarding the same aspects reported for carotid arteries, a frequent site of occurrence and development of atherosclerotic processes, is scarce [44]. Using ACE mRNA and ACE protein, Fukuhara et al. examined 24 endarterectomy specimens obtained from patients with severe carotid occlusive disease. With the help of in situ hybridization and immunohistochemistry, they identified ACE in smooth muscle cells, endothelial cells, macrophages, and lymphocytes. The ACE protein was mainly located in the intima, and the ACE staining increased with the complexity of atherosclerotic lesions, reaching a maximum level in the lesions with a high density of macrophages. Another important finding was that the microvessels in plaques were free of inflammatory cells [41]. ACE has a direct effect on inflammatory cells, which may be associated with the continuous development and increasing vulnerability of atherosclerotic plaques. Among the cellular effects induced in macrophages is the increased LDLoxidation process. Ang II influences the oxLDL receptor (LOX-1) activity in endothelial cells as well as lipid peroxidation or metalloproteinase production. Cellular NADPH oxidase and 15-lypoxygenase have an essential role in lipid peroxidation.

4. The role of angiotensin in the pathophysiology of atherosclerotic

On the other hand, inhibitors of phospholipases A2, C, and D antagonize this process, suggesting a potential involvement of phospholipid metabolites such as extracellular calcium ions [45]. Morawietz et al. demonstrated that Ang II regulates LOX-1 both in vivo and in vitro through AT1R and therefore long-term use of ACE inhibitors may have an antiatherosclerotic role [46]. De Cavanagh et al. conducted a study on 4month-old male rats to demonstrate that hypertension induces kidney mitochondrial dysfunction and to determine whether administrating an ACE inhibitor (ACE-I) agent may reverse these changes. The spontaneously hypertensive rats received candesartan 7.5 mg/kg daily, while the control group received water with no additions. The first group associated higher systolic blood pressure, proteinuria, and lower creatinine clearance compared with the control group. In addition, kidney mitochondria membrane potential, NO synthase, and cytochrome oxidase activities were diminished, this fact being associated with the finding that protective renal effect of candesartan in hypertension may be related to the improvement of mitochondrial function [47]. In another study, the same group of investigators demonstrated that losartan, an AT1R antagonist, improved the mitochondrial dysfunction and reduced mitochondrial H2O2 [48]. Ang II induces ROS in the cytoplasm and mitochondria of cardiomyocytes. While moderate Ang II stimulation via NADPH oxidase and mitochondriadependent mechanisms is associated with heart preconditioning, a prolonged effect leads to pathological changes [49]. Kimura et al. demonstrated that preconditioning effects of Ang II in ischemic reperfusion heart injury are mediated by cardiac mitochondria-derived ROS enhanced through NAD(P)H oxidase via JNK and p38 mitogen-activated protein kinase activation [49,50]. Redo´n et al. emphasized the idea that hypertensive patients have increased levels of oxidative stress and diminished levels of endogenous antioxidant enzyme action in peripheral mononuclear cells [51,52]. Laursen et al. demonstrated in an experimental model that Ang II mediates the vascular production of superoxide, while norepinephrine-induced hypertension was not associated with such molecular changes. It is known that the main source of superoxide in vascular tissues is an NADH/NADPH-dependent, membrane-bound oxidase activated by Ang II [53e55]. Ang II acts predominantly at the superoxide anion level (O
2 ) [56]. The oxidative stress is a trigger in the progression of various cardiovascular diseases through redox regulation of essential cellular processes, and therefore, it might be the target of antioxidant therapy [52,57]. Ang II interferes with the homeostatic mechanism in the vessel wall, disturbing the thrombosisefibrinolysis balance by contributing to endothelial dysfunction and inflammation. In an indirect manner, Ang II has an inhibitory effect on the molecules involved in the fibrinolysis process, which leads to an increased level of PAI-1 mRNA in the vascular smooth muscle cells. Ang II initiates and contributes actively to the progression of atherosclerotic lesions by promoting cell adhesion molecules by activating NF-kB. Ang II modulates plasminogen activation in the vascular wall by enhancing both plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2) expression [58].

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Ang II has an essential role in the induction of growth factors such as TGF-b1, platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), or basic fibroblast growth factor (bFGF) via different signaling pathways. Their effect on the arterial wall may be related to RAS. Herna´ndez-Presa et al. demonstrated that the administration of quinapril in atherosclerotic rabbits is associated with a decreased PDGF-B expression [59e63].

5. Interaction between angiotensin and other mediators of the atherosclerotic process A feature of endothelial dysfunction is the increased expression of the arterial vasoconstrictor endothelin. Endothelin-1 (ET-1) via activation of the smooth muscle endothelin receptor (ETA) has mitogenic and vasoconstrictor properties and is increased in the coronary circulation of patients with endothelial dysfunction. Ang II enhances ET-1 expression. ET-1 plays an important role in the development of endothelial dysfunction and progression of atherosclerosis [64], and long-lasting antagonism of the ETA receptor (ETAR) has a protective effect on atherosclerotic plaque progression [1]. ET-1 is known to be the most potent vasoconstrictor in vascular smooth muscle cells and contributes to cardiomyocyte hypertrophy secondary to Ang-II. ET-1 has various effects on the RAS including dose-dependent inhibition of renin synthesis and stimulation of aldosterone secretion. Insulin, catecholamines, cytokines, and components of the fibrinolysis cascade are humoral factors, which activate different signaling pathways that increase the vasoconstrictor effect. ET-1 has an inhibitory effect on renin (both in vivo and in vitro) but stimulates the secretion of aldosterone via direct stimulation of the adrenal cortex [65,66]. The connection between ET-1 and RAS has therapeutic implications, the involvement on the pathogenesis of hypertension drawing attention to the importance of developing a therapeutic strategy addressing both systems [65]. Morand-Contant et al. demonstrated the connection between Ang-II and ET-1 by demonstrating the upregulation of kinin B1 receptor under their effect [67]. Antioxidants cancel the vasoconstrictor effect and consequently increase the expression of kinin B1 receptor. Besides Ang II and ET-1, NF-kB and the oxidative stress also induce the upregulation of kinin B1. The potentiating effect of Ang II on kinin B1 through AT1R activation was previously demonstrated on rats submitted to a renin-dependent model of hypertension [68,69]. Fernandes et al. studied the influence of Ang II in modulating the in vivo expression of kinin B1 receptors by quantifying with real-time PCR the B1 mRNA levels in the heart, kidney and thoracic aorta. Losartan administration was associated with an AT1 receptor blockade and a significantly reduced protein expression, suggesting a potential correlation between the two factors [68]. Ang II stimulates the production of mitochondrial reactive oxygen species, the association of the two mechanisms leading to a more pronounced effect in terms

5. Interaction between angiotensin and other mediators

of endothelial dysfunction, cardiovascular, or renal modeling as well as inflammation and fibrosis [70]. The AT1R overstimulation leads to ROS overproduction through a redox-dependent pathway mediated by AT1R. Queliconi et al. demonstrated that the activation of the mitochondrial ATP-sensitive potassium channels ensures the integrated maintenance of the enzymatic activity of NADPH, as essential condition for Ang II to stimulate the mitochondrial ROS [71]. Mitochondria are an important source of ROS and have an essential role in cellular redox signaling in physiological conditions. By stimulating the mitochondria, Ang II determines the overproduction of ROS, which leads to oxidative stress [70,72]. New insights into the mechanisms of atherosclerosis are needed, and molecules that are involved in the process and could be therapeutic targets deserve further investigation. There is a pressing need for more specific markers for peripheral arterial disease, a blood test that would increase recognition of the disease and thus improve the clinical solution. It is possible that a biomarker with increased sensitivity and specificity for arterial disease may have systemic circulation but reflect the activity of local pathophysiological processes. Recently, the role of monocyte chemoattractant protein-1 (MCP-1) in promotion of atherosclerotic lesions has been studied, but has not been fully clarified. MCP-1 is part of the chemokine CC subfamily. Ang II enhances its expression and thus its chemotaxis and activates immune cells such as monocytes and T lymphocytes to the injured vascular wall [73,74]. Patients under treatment with Ang II receptor blockers have monocytes, which express less amount of MCP-1, leading to an attenuation of the inflammatory process. Atherosclerosis induces a systemic inflammation, which secondly activates the brain’s immune response. RAS and the central nervous system interact, both of them being involved in the pathophysiological mechanisms of hypertension. Some of the RAS components are generated de novo in different organs including the brain. This neurohormonal connection controls the sympathetic tone and the endocrine factors that control blood pressure [75]. Ang-II has a neuroplasticity role by inducing changes in the hypertensive response sensitization. The RAS components produced by the brain are involved in various paracrine, autocrine, or intracrine signaling pathways through neurons, astrocytes, and microglia functions [76,77]. Several nuclei of the central nervous system modulate the cardiovascular functions and fluid balance. Sumners et al. demonstrated that lamina terminalis, paraventricular hypothalamic nucleus, or solitary tract nucleus are areas with a high density of AT1R often innervated by axons made up of RAS components [78,79]. AT2R and masR are located in the proximity of cardiovascular nuclei in the brainstem and hypothalamus that express the AT1R [80e82]. Increasing sympathetic activity induces brain AT1R activation and consequently a hypertensive effect [80]. Midkine is a heparin-binding growth factor, which can be considered as a multifunctional cytokine due to its associations with vascular and inflammatory cell migration, proliferation, and angiogenesis, underlying pathophysiological processes of peripheral artery disease (PAD) [83].

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Hypertension, diabetes mellitus, obesity, and dyslipidemia are some of the cardiovascular risk factors that predispose to the development and maintenance of atherosclerotic processes. Over time, the presence of metabolic syndrome or its components leads to the development of an inflammatory status where midkine seems to play an increasingly important role, but further studies are needed to clarify the mechanisms of action. It is important to mention that midkine has been shown to regulate the RAS and that midkine participates in the cross-communication between kidney and lung having Ang II at the center, in 5/6 nephrectomized mice [84]. The countermeasure to peripheral ischemia includes neoangiogenesis. Such a process requires cellular orchestration involving endothelial cell proliferation and vascular collateralization. As demonstrated in midkine knockout animals, midkine can initiate neoangiogenesis under ischemia in nonmalignant tissues [85], and thus, high serum levels could indicate a link to neoangiogenesis. Conversely, low serum levels could indicate absence of neoangiogenesis. There are many stable marker biomarkers for cardiovascular disease in this category of patients, but none have been found to be applicable in practice. Clinically, mechanical vascular injury is followed by an inflammatory response causing neointima formation that may lead to restenosis after therapeutic intervention. Leukocytes play an important role in this context by secreting factors that promote smooth muscle cell migration and proliferation and maintain an inflammatory environment. Compared with control mice, neointima formation was almost absent in midkine-deficient mice [86]. This is consistent with the fact that leukocyte recruitment to the affected vascular wall was reduced in midkine-deficient mice compared with the control group. However, intraarterial administration of recombinant midkine restored neointima formation [86]. Endothelial cells of venous grafts implanted into rabbit arteries also expressed midkine. When grafts were treated with midkine siRNA, intimal thickness and leukocyte infiltration into the vascular wall were significantly reduced, suggesting that midkine promoted leukocyte infiltration into the vascular wall after intervention-associated vessel injury [87]. Autoantibodies are proteins produced by B cells against one or more of their own proteins, and several studies have revealed their involvement in the development of atherosclerosis as pro- or antiinflammatory factors. Angiotensin IIetype I receptor (AT1R) and endothelin-1 type A receptor (ETAR) autoantibodies are directed against AT1R and ETAR. The prevalence in healthy subjects is reported to be around 10%e15%, higher percentages being encountered in the case of patients waiting for transplantation (15%e40%) or in children born from mothers with a complicated pregnancy evolution [88]. Compared with Ang -II, AT1R autoantibodies have a superior vasoconstrictor effect [89,90]. In patients with overt cardiovascular disease and without concomitant autoimmune disease, there are numerous autoantibodies that predict a poor cardiovascular prognosis [91]. Some of these autoantibodies could directly influence atherosclerotic processes by activating immune receptors, signaling toward a pro- or antiinflammatory response. Studies supporting the prognostic value of the most relevant

5. Interaction between angiotensin and other mediators

autoantibodies to date have investigated antiphospholipid antibodies [92], antieheat shock protein [93,94], antiehigh-density lipoprotein/polypoprotein A-1 [95], and anti-LDL oxidase [96]. Mechanisms involved in the pathophysiological process range from endothelial dysfunction [96,97] to a direct role in atherothrombosis [98]. Their titers have previously been shown to be independent of classical risk factors, but there is a strong positive correlation between anti-AT1R and anti-ETAR concentration. ETAR and AT1R autoantibodies have vasoconstrictor, proinflammatory, and profibrotic effects on coronary microvascular circulation [88]. AT1R and ETAR are expressed in advanced atherosclerotic lesions in patients with severe peripheral arterial disease. Both receptors mediate unfavorable vasoconstriction and have proinflammatory, proproliferative, and profibrotic actions relevant to the pathophysiology of atherosclerosis. There are very few studies in the literature on the involvement of AT1R and ETAR autoantibodies in human disease. AT1R autoantibodies have been associated with preeclampsia and renal allograft rejection [99]. They stimulate NADPH-oxidase synthesis in various cell types, including vascular smooth muscle cells, resulting in increased reactive oxygen species production and oxidative damage. The presence of ETAR autoantibodies has been reported in patients with pulmonary hypertension [100]. In a recent study, most patients with systemic sclerosis developed antibodies with specificity for each of the two receptors, and higher antibody titers were relevant for late complications such as pulmonary hypertension, pulmonary fibrosis, and digital ulcers [101]. According to this study, AT1R and ETAR autoantibodies could contribute to the pathogenesis of the disease by connecting autoimmunity, endothelial dysfunction, and hypertension. Specific binding of autoantibodies to AT1R and ETAR from human microvascular endothelial cells was demonstrated by coimmunoprecipitation. Antibodies to each receptor were biologically active by inducing ERK phosphorylation and increasing tumor growth factor (TGF)-b gene expression in endothelial cell cultures. They show similarities to antiendothelial cell antibodies since endothelial cells express both receptors. Sasaki et al. [101] reported that angiogenesis, arteriogenesis, and blood flow recovery in response to experimental lower limb ischemia were severely impaired in AT receptor II type 1a knockout mice compared with wild-type mice. Pharmacological blockade of the AT1 receptor suppressed ischemia-induced angiogenesis. Previous studies have indicated that AT II may function as a proangiogenic factor, inducing vascular growth factor (VEGF) expression in vascular smooth muscle cells, stimulating endothelial cell proliferation, migration, and angiogenesis [102]. Therefore, the presence of an AT1R-blocking autoantibody would prevent ischemicinduced angiogenesis in the same manner as an ARB, minimizing the appearance of collateral vessels. It would be of interest to determine whether this angiogenic function is also modulated by hypoxia-induced factor (HIF)-1a, as is the suggested mechanism for midkine-induced angiogenesis in limb ischemia [103]. Transcriptional factor HIF-1a plays a central role in cellular adaptation to hypoxia, contributing to dysfunction in various components of atherosclerosis, increased local inflammation, and angiogenesis.

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Nickenig et al. reported that oxidized LDL amplifies AT1 receptor expression in vascular smooth muscle cells [102]. Gross et al. investigated the association between AT1R expression and the severity of atherosclerotic lesions [104]. A large body of evidence supports that endothelin-1 (ET-1) possesses a number of biological activities that lead to cardiovascular disease, including hypertension and atherosclerosis [105]. At the vascular level, ETAR present on vascular smooth muscle cells mediates vasoconstriction and cell proliferation. Apparently, ETAR expression is amplified during myocardial ischemia/reperfusion [106], and the ET-1/ETAR pathway promotes myocardial fibrosis by inducing cardiac fibroblast proliferation, adhesion molecule expression, and extracellular matrix deposition [107,108]. These effects contribute to neointima formation after percutaneous coronary angioplasty [109], while vascular remodeling is markedly attenuated by treatment with a selective ETAR antagonist [110]. Innate and adaptive immune responses have been identified in atherosclerosis, with cholesterol particles carried by low-density lipoproteins generating inflammation, T cell activation, and antibody production during disease progression. Components of adaptive immunity are present in lesions throughout the atherosclerotic course, and several studies have indicated an important role of antigen-specific adaptive immune responses in the atherogenic process. This study provides evidence for the association between apparent endothelial dysfunction and alterations in the immune system. Atherosclerosis has many similarities with other chronic autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, vasculitis, and type 1 diabetes mellitus. All show evidence of activation of macrophages, lymphocytes, and endothelial cells and the increase of inflammatory cytokines. These events may favor the production of autoantibodies and accelerate arterial thrombosis. Midkine is an important factor in patients with advanced atherosclerosis and may be one of the missing links in the pathomechanism of this disease. Just as midkine is expressed in cardiomyocytes under ischemic conditions and overexpressed after myocardial infarction, probably the same mechanism is involved in peripheral ischemia, with higher midkine values in acute ischemia. Of particular interest is the inverse association with antibody-induced signaling against AT1R and ETAR. Midkine induces ACE expression in microvascular endothelial cells as a regulator of RAS. Significantly lower serum midkine levels were found in cardiac transplant patients treated with ACEI or ARB. The same mechanism could underlie for AT1R and ETAR antibodies, which are inversely correlated with midkine levels. The corroborating data bring together the RAS and the endothelin system as hallmark effectors in atherosclerosis, and a mediator of angiogenesis (Fig. 9.4). A possible explanation for this phenomenon would be the “inner balance” of the atherosclerotic process as a multifactorial disease. The more important the general state of inflammation, angiogenesis, and proliferation in the vascular wall, represented by high levels of midkine, the lower the activation of the immune system involved in atheroprogression, in this case represented by functional autoantibodies against wellknown effectors of the atherogenic process.

6. Angiotensindclinical and therapeutical implications

Recent studies reveal various novel cardiac biomarkers such as midregional proadrenomedullin (MR-proADM), midkine, and stromelysin2 (ST2) associated with CVD such as heart failure and atherosclerosis both in the form of chronic coronary syndrome or acute coronary syndrome [111]. Over the past years, great progress has been made regarding the identification and widespread use of biomarkers for early diagnosis of peripheral artery disease.

6. Angiotensindclinical and therapeutical implications ACE-Is are widely used in various cardiovascular diseases. ACE-I has its effects on RAS, but not directly related to renin levels in the blood. ACE-I also interferes with the bradykinin metabolism and inhibits the formation or degradation of other vasoactive substances such as substance P [112e114]. Captopril has been the first clinically available ACE-I, developed for the treatment of hypertension in patients with renin-dependent pathophysiology [115]. Endothelial dysfunction has prognostic value in relation to the occurrence of an acute cardiovascular event, and therefore, the administration of ACE-I is associated with reduced ET-1 gene expression and an increased production of NO necessary to maintain the endothelial function. Nitric oxide has multiple roles in the atherosclerotic process such as a diminished level of ET-1 through soluble guanylate cyclase activation and increased cellular generation of cGMP, which decreases the release of ET-1 and pre-pro-ET-1 mRNA [116]. ACE-Is are used in myocardial infarction to reduce cardiac remodeling and decrease the rate of mortality by antagonizing the sympathetic nerve stimulation, balancing oxygen demand and supply, and inhibiting the degradation of bradykinin [117]. On the assumption that ET-1 determines endothelial dysfunction in the coronary circulation through inflammation, a reduced NO activity, and increased oxidative stress, Aliska et al. demonstrated that ramipril attenuates ET-1 expression in ratinduced myocardial infarction, unfortunately without a statistically significance with the control group [118]. In another study, Bayir et al. demonstrated the beneficial role of ramipril in patients with acute myocardial infarction by decreasing the serum brain natriuretic peptide (BNP), an important marker associated with cardiac failure [119], suggesting a protective effect by inhibiting the RAS system. Left ventricular hypertrophy, fibrosis, diastolic dysfunction, or heart failure are some of the “macro” consequences of Ang II overproduction. Ang II acts directly on cardiomyocytes via various signaling pathways and interferes with apoptosis, mitochondrial dysfunction, or autophagy [120]. Kim et al. demonstrated that in rat arteries, ACE-I inhibits the ERK/MAPKs signaling pathway involved in apoptosis and cell proliferation [121]. The current guidelines of both American Heart Association/American College of Cardiology (AHA/ACC) and the European Society of Cardiology (ESC) recommend the use of ACE-I as first-line antihypertensive therapy [122,123]. In patients with heart failure with reduced ejection fraction, ACE-I reduces overall mortality

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even in asymptomatic patients [124]. Based on the studies of ACE-I versus placebo that showed a significant reduction in cardiovascular events and mortality rates, guidelines strongly recommend the use of ACE-I for patients with stable coronary artery disease without heart failure [125]. The Heart Outcomes Prevention Evaluation (HOPE) study [126], the European trial on Reduction Of cardiac events with Perindopril among patients with stable coronary Artery disease (EUROPA) [127], and the Prevention of Events with ACE inhibition (PEACE) trial [128] demonstrated the beneficial effect of ACE-I in terms of total mortality rates and fatal or nonfatal cardiovascular events in patients with vascular disease and normal left ventricular function [129]. In a combined analysis of the three trials, Dagenais et al. concluded that the use of ACE-I is associated with an important reduction of vascular events in patients with atherosclerosis with or without heart failure. ACE-I significantly reduced the all-cause mortality (P ¼ .0007), the cardiovascular mortality (P ¼ .0002), the stroke-related risk (P ¼ .0004), the heart failure risk (P ¼ .0007), and the coronary artery bypass surgery related risk (P ¼ .0036), but not the risk of a percutaneous coronary intervention (P ¼ .481) [130]. ACE-I prevents cardiac remodeling after the occurrence of a myocardial infarction. In the Perindopril and Remodeling in Elderly with Acute Myocardial infarction (PREAMI) trial, 1252 patients (age 65 years or more) with a left ventricular ejection fraction of 40% and above and recent acute myocardial infarction were randomized to receive perindopril erbumine or placebo (8 mg/d) for 12 months. At the 1-year follow-up, investigators concluded that perindopril reduced the composite primary endpoint of death, heart failure hospitalizations, or cardiac remodeling by 38% (P ¼ .001) versus placebo [131]. The Quinapril Ischemic Event Trial (QUIET) [132], Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study [133], and Ischemia Management With Accupril PostBypass Graft via Inhibition of the Converting Enzyme (IMAGINE) trial [134] showed no additional benefit of ACE-I compared with placebo. The baseline risk of the patients enrolled influenced the overall results, as benefits were only seen in trials with high baseline risk such as HOPE and EUROPA [125]. Bangalore et al. performed a metaanalysis in which 198,275 patients from 24 clinical trials were included. The use of ACE-I was associated with a reduction of all-cause mortality risk (OR 0.84, 95% CI 0.72e0.98), cardiovascular mortality (OR 0.74, 95% CI 0.59e0.94), myocardial infarction (OR 0.82, 95% CI 0.76e0.88), stroke, angina, heart failure, and revascularization compared with the placebo groups, but not when compared with active controls [125].

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CHAPTER

ACE2 in pulmonary diseases

10 Qing Lin1, Hongpeng Jia2

1

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; 2Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland

1. Introduction Angiotensin-converting enzyme 2 (ACE2) is a relatively new member of renine angiotensin system (RAS). It primarily functions as a powerful negative regulator of RAS to gauge RAS activity and to avoid the detrimental consequences of an over activated RAS [1,2]. (Fig. 10.1) Moreover, ACE2 is the cognate receptor for severe acute respiratory syndrome coronavirus 1 and 2 (SARS-CoV, SARS-CoV-2)

FIGURE 10.1 Schematic representation of the role of ACE2 in renineangiotensin system (RAS) and kininekallidin system (KKS). Angiotensin. https://doi.org/10.1016/B978-0-323-99618-1.00021-0 Copyright © 2023 Elsevier Inc. All rights reserved.

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[3,4], which makes ACE2 a molecule of highly prioritized research target in efforts to cut off the two pandemics since the beginning of this century. As a zinc metallopeptidase, human ACE2 gene is located on X chromosome (Xp22.2). However, there is no definitive sex-determined preferential expression or induction of ACE2 gene in naı¨ve or diseased conditions being reported, suggesting a mosaic allele gene expression. The mRNA of ACE2 is derived from 18 exons of human genome. ACE2 gene is expressed in many cell types, flanking from neuro system to reproductive tracts [5], which is a reason why COVID-19 affects many organs, tissues, and cells. ACE2 is a mono carboxypeptidase and executes its negative regulation of RAS mainly through modulating the Ang II/AT1R and Ang-(1e7)/Mas1 axis [6]. Ang(1e7) is an active metabolite of angiotensin II (Ang II) by, predominantly, ACE2 cleaving one amino acid from the C terminal of Ang II. Therefore, balanced Ang II/AT1R versus Ang-(1e7)/Mas1R is the target of ACE2 to excise its regulatory function in RAS [7]. After a few decades of research, more substrates of ACE2 are revealed, including neocasomorphin, des-Arg [8]-bradykinin, b-casomorphin, Apelin13 and 36, and dynorphin A [9]. However, the physiological and pathophysiological consequences of these substrates regulated by ACE2 are still short in the detailed investigation. Owing to the development in understanding ACE2 biology, the downstream signaling pathways related to ACE2 functions are revealed in recent years, especially after the beginning of COVID-19 pandemic (Fig. 10.2).

FIGURE 10.2 Signaling cascades triggered by Ang II and Ang-(1e7).

2. ACE2 and pulmonary hypertension

Conventionally, there are two forms of ACE2 protein in human and animals: soluble and cell membraneebound ACE2. The former is a product of the latter through cleavage by A disintegrin and metalloprotease 17 (ADAM17), aka, tumor necrosis factor alphaeconverting enzyme (TACE) near the boundary of ectodomain and transmembrane domain. Although Adam10 is also proposed to be able to cleave ACE2, the predominant sheddase of ACE2 is considered ADAM 17 or TACE [8,10]. The soluble and membrane-bound ACE2 both can execute enzymatic activity and bind to SARS-CoV and SARS-CoV-2 viruses, but only the membrane-bound ACE2 is able to function as the cognate receptor for the viruses [10]. However, controversy arises in that Yeung et al. reported that soluble ACE2 is capable of mediating cell entry of SARS-CoV-2 via interaction with proteins related to the RAS [11]. In 2020, a unique form of ACE2 is discovered by Onabajo and colleagues. They reported that a novel and transcriptionally independent isoform of ACE2, delta ACE2 (dACE2), exists as a truncated form of ACE2 (lacking 356 amino-terminal amino acids). dACE2, not prototype ACE2, is an interferon-stimulated gene (ISG). Most importantly, dACE2, due to the truncation at N-terminal, is unable to binding SARS-CoV-2, neither does it function as carboxypeptidase [12]. However, the exact biological function of this new form of ACE2 is unclear. Although ACE2 is a such important player in RAS activation, much of research attention of ACE2 has focused on its past-unknown function as the cognate receptor for severe acute respiratory syndrome coronaviruses (SARS-CoV and SARS-CoV-2) since the past decades. Moreover, many reports in recent years indicated that ACE2 plays a role in a variety of disease settings, including pulmonary diseases. In this chapter, we will discuss the updated understanding the role of ACE2 in the pathogenesis of pulmonary diseases.

2. ACE2 and pulmonary hypertension The pathogenesis of pulmonary hypertension (PH) features pulmonary vascular remodeling, increases in pulmonary artery pressure, and right heart failure [13]. In humans, severe PH is characterized by plexiform lesions that contain phenotypically altered pulmonary vascular smooth muscle cells (SMCs) and endothelial cells (ECs) [14,15]. Activation of infiltrating inflammatory cells is the major determinant of pathological vascular remodeling in PH [16,17]. The RAS plays a role in the pathogenesis of PH. Ang II promotes the development of PH by inducing vasoconstriction, SMC proliferation, and cell/tissue inflammation [18,19]. Studies have indicated that an imbalance between the mechanisms of the ACEeAng IIeAT1R and the ACE2eAng-(1e7)eMas pathways in the pulmonary circulation leads to the development of PH [20]. Exogenous expression ACE2 or Ang-(1e7) blocks experimental PH by suppressing the Ang II-induced inflammation and oxidative stress [21e23], indicating ACE2 activation as an anti-PH therapeutic approach. Indeed, overexpression of ACE2 gene by transfecting lentiviral directly attenuated PH in rodents treated with chronic hypoxia or monocrotaline (MCT) in vivo

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[24e26] and inhibited the proliferation and migration of rat isolated pulmonary arterial (PA)-SMCs in vitro [24]. The specific ACE2 activator diminazene aceturate (DIZE) prevented PH development in the rat models treated by MCT, hypoxia, or bleomycin [27,28]. These beneficial effects of enhancing the enzymatic activity of ACE2 by DIZE were abolished by C-16, an ACE2 inhibitor [27]. Mechanistically, ACE2 signaling has proregenerative activities to rescue the dysfunction and impaired migration of bone marrowederived angiogenic progenitor cells in the PH rats [27]. Using another ACE2 activatordNCP-2454 [29], studies found that ACE2 activation suppressed JAK/STAT and TGF-b cascades by restoring caveolin-1 to produce antiinflammatory and antifibrotic effects in the rat MCT model. ACE2 also rescued the EC dysfunction by increasing eNOS Ser1177 phosphorylation and eNOS Thr495 dephosphorylation in these vascular cells to promote NO release [30,31]. In the bleomycin-induced mouse PH model, continuous administration of recombinant human ACE2 protein treatment (via osmotic pump) could be an effective therapeutic [32]. It increased protein levels of plasma superoxide dismutase (PSD)-2, which is able to decrease vascular SMC proliferation and neointimal formation [32]. Further gain- and loss-of-ACE2 function studies using ACE2 activator (resorcinolnaphthalein) and inhibitor (MLN-4760) revealed that ACE2 induces pulmonary arterial cell apoptosis through Hippo/LATS1/Yap pathway to attenuate pulmonary vascular remodeling in the PH rat model developed by MCT combined with left pneumonectomy [33]. ACE2 also promoted SMC apoptosis through inhibiting focal adhesion kinase (FAO) [34]. Recently, in the PH models using a global ACE2 knock-in mouse line, it further demonstrated that ACE2 overexpression prevented the hypoxia-induced gut pathology, regulated microbial communities, rebalanced the dysfunctional brainegutelung axis, and thereby protected against PH [35,36]. Further studies revealed the regulatory network of ACE2 signaling in PH. The anti-PH activities of ACE2 could be regulated by AMP-activated protein kinase (AMPK). In the studies using gain-of-function ACE2 S680D knock-in and lossof-function ACE2 global knock-out mouse lines, AMPK induced the phosphorylation of ACE2 Ser680 to enhance ACE2 stability in pulmonary vascular ECs for endothelial homeostasis [31]. Using transgenic mice overexpressing dephosphorylated or deubiquitinated ACE2 showed that murine double minute 2 mediated the ubiquitination of ACE2 at K788 [37]. The maladapted phosphorylation and ubiquitination of ACE2 is causative of dysfunction of pulmonary arterial ECs from patients with idiopathic pulmonary arterial hypertension (PAH) or from mouse model of SU5416/hypoxia-induced PH [37]. Intriguingly, microvesicles derived from bone marrow mesenchymal stem cells (MSCs) activated ACE2 signaling to alleviate PH in MCT rats [38]. The hypoxia-inducible factor 1a (HIF-1a) indirectly inhibits ACE2 in hypoxia lung, which is mediated by MiRNA let-7b [39]. The gene transcription of ACE2 suppressed by HIF-1a-let-7b was indicated as a mechanism of PH [39]. Regulation of ACE2 is also a mechanism that underlies the anti-PH effects of other drugs including magnolol [40] and fasudil [41,42] in the rodent PH experimental models induced by MCT or chronic hypoxia. The oral delivery of plasmids

3. ACE2 and asthma

containing ACE2 expression bioencapsulated within plant cells has been developed and validated for the effectiveness of ACE2 overexpression and PH attenuation in MCT PH rats [43]. In addition to the classic rodent models, the beneficial effects of ACE2 have also been reported in other rat PH models induced by (1) chronic cigarette exposure [44]; (2) ascending aortic banding (PH secondary to left ventricular dysfunction) [45]; and (3) left pneumonectomy combined SU5416 injection [46]. In humans, expression of ACE2 and ADAM17 (a disintegrin that cleaves ACE2 from cell membrane) is upregulated in patients with PAH undergoing lung transplantation in a metaanalysis performed on lung transcriptomes [47]. The changes are similar in idiopathic PAH, connective tissue disease/systemic sclerosis (SSc)
associated PAH, and congenital heart disease (CHD)
associated PAH [47]. However, ACE2 activity was significantly reduced in PAH patients [48]. As the primary receptor of SARS-CoV2, the dysfunctional ACE2 may be responsible for the PH caused by COVID-19 and lead to the secondary refractory hypoxemia [49]. Moreover, phase IIa clinical trial has tested the treatment of rhACE2 (GSK2586881) in PAH patients and found that augmentation of ACE2 was well tolerated, associated with improved pulmonary hemodynamics and reduced markers of oxidant and inflammatory mediators [50]. Further clinical studies targeting ACE2 as a therapeutic in PAH are ongoing [20,50].

3. ACE2 and asthma Asthma shares some key pathological features with PH, including increased RVSP and induction of vascular inflammation and remodeling [51,52]. ACE2 expression was suppressed in the local airway and lung samples of rodent models in asthma pathogenesis [53,54]. At the functional levels, the enzymatic activity of ACE2 modulated allergic inflammation in the asthma mouse model induced by house dust mites (HDM) [53]. ACE2 activator DIZE suppressed the HDM-induced airway hyperresponsiveness and the production of Th2 cytokines IL-5, IL-13, and IL-33 in the lungs [53]. In the rat asthma model induced by ovalbumin (OVA), DIZE prevented asthma progression by altering AKT, p38, NF-kB, and other inflammatory cytokines including IL-1b [54]. In humans, asthma can be divided into different endotypes including Th2 high/ eosinophilic, Th17/neutrophilic, Th2/Th17/mixed inflammation, and paucigranulocytic [55]. Consistent with animal data, allergen exposure, allergic sensitization, and high IgE led to lower ACE2 expression in the nasal and bronchial epithelium [56,57]. ACE2 was predominantly expressed in secretory cells and ciliated cells of asthma patients [58], and its expression was regulated by Th1/Th2/Th17 cytokines. IL-4 and IL-13 could downregulate ACE2 in the Th2-high asthma [57e61]. In contrast, in the Th2-low asthma, Th1/Th17 cytokines TNF, IL-12, IL17A, IL-8, IL-19, and IFNs upregulated ACE2 expression in airway epithelial cells [58e61]. Circulating soluble ACE2 (sACE2, the competitive interceptor of membrane ACE2) [60] and ADAM-17 [62] were elevated in asthmatic patients.

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Intriguingly, ACE2 levels were significantly increased in sputum of severe neutrophilic asthma compared with mildemoderate asthma [63]. In these Th2-low asthma patients, increased expression of ACE2 was positively associated with other Th2low phenotypes including obesity, smoking, and age-associated asthma [62,64]. Other confounding factors such as male sex, African American ethnicity, and a history of diabetes mellitus may affect ACE2 expression among asthmatics [63e65]. Treatments of asthma also altered ACE2 levels. Low-dose short-term inhaled corticosteroids (ICSs) reduced, whereas long-term ICS treatment increased, airway ACE2 expression in asthmatics [63,64,66]. Interestingly, other studies analyzed ACE2 gene expression in primary human bronchial epithelial cells, bronchial biopsies, and BAL fluid of healthy children/ adults and adult asthma patients [5] and did not find significant difference in ACE2 expression in these samples between control and asthma patients [5]. The use of different human samples, and patients with multiple characteristics (such as smoking asthmatic patients as discussed before), may present a difference in lung ACE2 levels [60]. It might also be related to different endotypes (Th1/Th2/ Th17 tissue inflammation) of asthma.

4. ACE2 and pulmonary fibrosis Lung fibrosis is often complicated by PH and promoted by Th2 and Th17 inflammation. Given that ACE2 exhibits antiPH activities and its expression is regulated by Th2/Th17, it suggests the implication of ACE2 in pulmonary fibrogenesis. In the rat and mouse experimental lung fibrosis induced by bleomycin, ACE2 expression and activity were decreased [67]. Intratracheal administration of ACE2-specific siRNAs or competitive inhibitor DX600 increased lung collagen in the bleomycin-treated mice [67]. The exogenous recombinant human [67] or mouse [68] proteins of ACE2 attenuated collagen accumulation, suppressed Ang II and its precursor angiotensin, and decreased the levels of leukocyte common antigen and pulmonary surfactant-associated protein A in the local lung of the bleomycin rodent models. The antifibrotic effects of ACE2 were also demonstrated in the bleomycin-induced rat PH model as collagen deposition was assuaged by intratracheally administration of lentiviral packaged ACE2 cDNA [25]. Using genemodified mice, ACE2 gene deletion worsens bleomycin-induced lung fibrosis more so in males than females [69]. Several downstream pathways mediating the antifibrotic effects of ACE2 have been identified in the bleomycin-treated rodent models: ACE2 inhibited the RhoA/Rock pathway by reducing NOX4-derived ROS [70] to mitigate lung fibroblast migration and reduce expression of TGF-b1, a-SMA, beta-prolyl-4-hydroxylase (P4H, the key enzyme of collagen synthesis), MMP-1, and MMP-2 [68,71]. ACE2 activation mediated the antifibrotic effects of the Chinese herbal extracts Tanshinone IIA [72] and osthole [73] in bleomycintreated rats. ACE2 also interacted with the antifibrotic peptide acetyl-serylaspartyl-lysyl-proline (Ac-SDKP) to inhibit lung fibrosis in rats exposed to silica

5. ACE2 and lung cancer

[74]. Intriguingly, human umbilical cord MSCs with ACE2 overexpression (gene transfection by lentiviral vector) exhibited therapeutic effects on the bleomycininduced lung fibrosis in mice [75]. In humans, lentivirus-mediated ACE2 overexpression in fetal lung (HFL)-1 cells (fibroblasts) inhibited the Ang II-induced MAPK/NF-kB pathway, thereby attenuating a-collagen I production [76]. In the alveolar epithelial cell lines A549 and MLE-12, ACE2 expression and function were abrogated in the proliferating condition versus quiescence [77], which was dependent on JNK activation [77]. Consistently, in lung biopsy specimens from patients with idiopathic pulmonary fibrosis (IPF), ACE-2 mRNA and enzyme activity were severely downregulated or absent [67], especially in the actively proliferating alveolar epithelia [77]. There are studies showing the upregulation of ACE2 in the progression of pulmonary fibrosis. It is found that in non-IPF patients, cells expressing ACE2 were limited to human alveolar cells. In IPF patients, ACE2 largely upregulated and extended to be in the fibroblast-specific protein 1 (FSP-1)epositive lung fibroblasts in human pulmonary fibrotic tissue [78]. Consistently, in mouse model, ACE2 expression in FSP-1-positive lung fibroblasts was observed in bleomycin-treated group and further upregulated in the group treated with bleomycin combined with particulate matter (PM) exposureda more severe pulmonary fibrosis model [78]. The severity of pulmonary fibrosis and ACE2 expression in this bleomycin þ PM model was dependent on KC(IL-8)/CXCR1/2 signaling [78]. Upregulation of ACE2 was also detected in the small airway epithelium and in alveolar areas of IPF compared with healthy control [79]. Pulmonary ACE2 expression was increased by cigarette smoking, which is a major driving factor in patients with IPF [79,80], indicating the implication of ACE2 in IPF progression. The dynamic variation [81] and the cell cycleedependent regulation [77] of pulmonary ACE2 may explain the different expression pattern of this protective enzyme in the development of pulmonary fibrosis, which requires further investigation for elucidation.

5. ACE2 and lung cancer PH bears some resemblance to cancer, as pulmonary vascular cells acquire cancerlike traits including excessive proliferation and resistance to apoptosis [82]. The anti-PH role of ACE2 suggests its antitumor effects. ACE2 expression decreased in nonesmall-cell lung cancer (NSCLC) tissues than the matching nonmalignant controls. Overexpression of ACE2 inhibited the growth, migration, and the production of VEGF, MMP-2, and MMP-9 in lung carcinoma cell line A549 in vitro [83,84] and in the A549 tumor tissue xenografts in vivo [85]. Further in vitro studies revealed that ACE2 attenuated the NSCLC metastasis through inhibition of epitheliale mesenchymal transition [86,87]. In addition to its antitumorigenic function, ACE2 also has biomarker potential as its serum levels was associated with postoperative morbidities after major pulmonary resection in NSCLC patients [88]. In computational analyses of the Cancer

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Genome Atlas, upregulation of ACE2 in lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) was found, and high expression of ACE2 was associated with low survival rate in these lung cancer patients, supporting ACE2 as the biomarker of lung cancers [89]. Studies accessing the databases of genome, protein, and pathology confirmed the biomarker potential of ACE2, which is responsible for the higher susceptibility and fatality of lung cancer patients toward COVID-19 [90]. Seven transcription factors (TFs) including WT1, STAT3, YY1, AREB6, ERG, GKLF, and GATA2 were identified as possible inducers of ACE2 transcription in lung tumors [91]. ACE2 was also expressed at higher levels in lung metastases from primary colorectal cancer than in normal lung tissues [92]. Single-cell RNA sequencing analysis of lung tissues of primary early-stage LUAD (I-IIIA) revealed that ACE2 levels were highest in normal alveolar type 2 cells [93]. The ACE2positive LUAD cells highly expressed the genes of chronic obstructive pulmonary disease (COPD)eassociated HHIP and scavengers CD36 and DMBT1 [93]. Other studies found that ACE2 expression levels were higher at resection margins of lung cancer survivors with COVID-19 [94]. ACE2 (lentivirus-mediated) overexpression in A549 reduced the viability and migratory potential of these human lung cancer cells [95], supporting the antitumorigenic effects of ACE2 in lung cancer [95]. However, studies on small-cell lung cancer (SCLC) reported that ACE2 was highly related to the drug resistance [96] and that ACE2 was a direct target of miR-181b in SCLC cells (primary PBMCs from SCLC patients or the NCI-H446 cell line) [96]. Further studies on the role of ACE2 in tumorigenicity of lung cancers are warranted.

6. ACE2 and chronic obstructive pulmonary disease COPD, including chronic bronchitis and emphysema, is the most common chronic lung condition in the world [97] and the most common cause of secondary PH [98]. COPD could be a driving factor in lung cancer [99]. The previously discussed colocalization of ACE2 with COPD-associated HHIP in LUAD cells [93] suggests a role of ACE2 in COPD. Chronic cigarette smokingeinduced airway hyperresponsiveness is the main cause of COPD [15]. Increased ACE2 expression in small airway epithelium and alveolar areas has been observed in smokers (including electronic cigarette, with or without nicotine) and patients with COPD [5,79,80,100e105], further indicating the implication of ACE2 in COPD pathogenesis. Overweight COPD patients have even more ACE2 bronchial epithelial expression than those without overweight [106]. Concomitantly, the levels of protective sACE2 were significantly reduced in COPD plasma compared with healthy control [107]. In experimental rodent models, ACE2 expression was decreased in COPD rat lung [108]. Overexpressing ACE2 in rat trachea significantly improved the lung function and pathological manifestations of COPD [108]. ACE2 activation attenuated the elevation of oxidative stress indicators malondialdehyde (MDA) and reactive oxygen species (ROS) and downregulated the proinflammatory pathways TNF-a, IL2, IL-1b, NF-kB, and p38 MAPK in COPD rats [108]. Decreased ACE2 was also

7. ACE2 and acute lung injury

observed in the rat CDPD model induced by long-term exposure to PM1 (the unconcentrated traffic-related air pollution) [109]. In these rats with emphysema, reduced ACE2 expression in lung was associated with increased markers of oxidative stress/ inflammation including 8-isoprostane, IL-6, and caspase-3 [109], signifying the altered ACE2 as a mechanism of air pollutioneinduced COPD. The ACE2 expression and function were regulated by several pathways in COPD development. Miz1 is a negative regulator of NF-kB signaling [110]. The mice with lung epithelial cellespecific deficiency of Miz1 spontaneously develop progressive COPD [110]. The COPD phenotype in these mice was associated with ACE2 upregulation [110]. Further study revelated that Miz1 directly binds to and represses the promoter of ACE2 in mouse and human lung epithelial cells [111]. The downregulated Miz1 in smokers and COPD patients thus is likely a molecular mechanism of upregulated ACE2 observed in the COPD patients and mice [111]. ICSs are widely used in COPD [112]. In the mouse COPD models or in airway epithelial cell cultures from COPD patients, ICS therapies reduced local pulmonary ACE2 expression through suppression of type I IFN [112]. The upregulation of ACE2 in the small airways of smokers and COPD patients may ascribe to the dysregulation of endocytic machinery, given the association of ACE2 with endocytic vacuoles including EEA1þ early and RAB7/cathepsin-Lþ late endosomes and LAMP-1þ lysosomes [113]. In smoker and COPD lung tissues, the activated presence of ACE2 was also correlated with the RNA-binding protein human antigen R (HuR) and its encoded gene ELAVL1 [114]. The HuR protein bound to ACE2 mRNA is thus likely a mechanism regulating ACE2 expression in COPD.

7. ACE2 and acute lung injury Because of its protective properties, ACE2 has been implicated in other lung injury conditions especially the acute lung injury (ALI). ACE2 deficiency exaggerated LPS-induced ALI in the gene-modified mice [115]. ACE2 agonist DIZE alleviated ALI induced by limb ischemia reperfusion (LIR) in mice [116]. This LIR-induced lung injury was ameliorated in the transgenic mice with global overexpression of human ACE2 [116]. The beneficial effects of ACE2 were also reported in the PM2.5induced ALI mouse model [117], as ACE2 gene knockout increased pulmonary levels of p-STAT3 and p-ERK1/2 and attenuated the resolution of pulmonary inflammation in these ALI mice [117]. In the cell culture study, primary human pulmonary microvascular (PMV)-ECs were treated with LPS as the in vitro ALI model [118]. The bone marrowederived MSCs overexpressing ACE2 (lentiviral vectore mediated) reversed the dysfunction and enhanced the viability of these injured lung ECs (through coculture) [118], further demonstrating the prorepair activities of ACE2 in ALI. Mechanistically, ACE2 produced by airway epithelial cells (from human or from the LPS-induced ALI mice) cleaved its substrate des-Arg9 bradykinin (DABK) to abrogate the bradykinin receptor B1 (BKB1R) [115]. Through modulating

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DABK/BKB1R axis signaling, ACE2 ameliorated ALI pathogenesis by suppressing NF-kB, reducing the expression of proinflammatory chemokines/cytokines, and diminishing neutrophil infiltration in the ALI lung [115]. ACE2 protein treatment antagonized the activities of VEGF and placental growth factor (PLGF) to reduce lung vessel permeability and improve lung function in the bleomycin-induced ALI mouse model [119,120]. In the ALI mouse model, lung ACE2 expression was decreased by LPS [121], and ACE2 systematic administration exhibited beneficial effects against LPS-induced ALI by inhibiting the TLR4 pathway [121]. ACE2 could be activated by lipoxin A4 in the LPS-induced ALI to inhibit NF-kB and decrease TNF-a, IL-1b, and ROS while increasing IL-10 in mouse lung [122]. ACE2 also mediated the antiinflammatory effects of Chinese herbal extract sini decoction in ALI mouse models induced by intratracheal infusion of Escherichia coli [123] or sepsis (by intraperitoneal injection of LPS) [124]. Glycyrrhizic acid alleviated the LPS-induced ALI by activating ACE2 [125]. Given that glycyrrhizic acid is a direct inhibitor of the key damage-associated molecular pattern molecule HMGB1 [126], it suggests a role of HMGB1 in regulating the beneficial effects of ACE2 in ALI. In addition, ACE2 activation affected the pathophysiological process of virusinduced ALI [127]. In a mouse acute lung injury model induced by SARS-CoV spike protein, which mimicked the active SARS-CoV-mediated lung injury, spike protein bound to ACE2, subsequently downregulated ACE2 protein expression and resulted in worsened acid aspiration pneumonia [128]. At the molecular level, ACE2 participated in virus-induced ALI by interacting with TNF, MAPK, and NOTCH signaling pathways and was linked with high confidence to gene products that have important functions in the pulmonary epithelium including Rnf128, Muc5b, and Tmprss2 [129]. The role of ACE2 in the virus-induced lung pathologies particularly the COVID-19 was further discussed in the following section.

8. ACE2 and COVID-19 The outbreak of coronavirus disease 2019 (COVID-19) caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a global threat to not only public health but also the world economy. A main feature of COVID-19 is lung inflammation and respiratory failure caused by an overactive immune response known as a cytokine storm [2]. ACE2 is a functional receptor that acts as a portal of entry for SARS-CoV-2 [4]. The SARS-CoV-2 interface interacts with host tissues through its surface ectodomain spike glycoprotein communicating with ACE2. This synergistic complex then becomes primed by the cellular serine protease TMPRSS2 facilitating direct viral entry into the cell via endocytosis [4,130]. ACE2 from the surface cell membrane then will be cleaved by the metallopeptidase ADAM-17 [130]. SARS-CoV-2 could exploit upregulation of ACE2 to provide further cellular targets for entry and thereby enhance infection [131]. Host ACE2 also undergoes endocytosis or shedding when the SARS-CoV-2 spike proteins are cleaved on viral

8. ACE2 and COVID-19

entry. As a result, ACE2 expression decreases, reducing the ability of the host to balance the RAS [130]. Dysregulated RAS may lead to exacerbated inflammation [130] and the possibly subsequent long-term pulmonary fibrosis [132]. Moreover, losing the protective and antiinflammatory activities of ACE2 is considered as the critical mechanism facilitating the uncontrolled cytokine storm, which is main reason of mortality in the COVID-19 patients [133]. The clinical observation seems to suggest that the expression level of ACE2 at the site of infection is a determinant of viral entry and infectivity. Indeed, several reports indicated that the severity of COVID-19 is related to advanced age, which correlates with higher expression of ACE2 gene in airway and the lung [134,135]. However, the relationship between ACE2 expression level and severity of COVID-19 remains uncertain due to, in part, lack of proper disease models. Several expression surveys show a gradient of ACE2 expression in the upper and lower airways and terminal airspace compartment [5,136e138]. The highest compartmental cellespecific expression is seen in ciliated cells of the proximal airway and the alveolar type II cells of the distal lung [139]. The binding of SARS-CoV2 to ACE2 is distinct from the sister strains of SARS-CoV, and NL63 in terms of interaction strengthens between the receptor and respective RBD [140e143], other coronaviruses that use this receptor but cause severe and minor lung morbidity, respectively. In addition, the coreceptor requirements of the viruse ACE2 complex are cell specific with differential use of TMPRSS2 or cathepsin L [144,145]. Transmembrane serine protease 2 (TMPRSS2), lysosomal cathepsin, and furin appear essential for SARS-CoV-2 virus processing, and entry into the cells, which has a significant impact on the state of viral spike protein, is complexed with ACE2 [4,144,146,147]. Although reports indicate that TMPRSS2 can cleave ACE2 [148], the interactions between ACE2 and TMPRSS2, or furin and cathepsin after the viral spike protein binds ACE2, have yet to be further investigated. Preclinical and whole-cell studies showing virus triggered the shedding of the ACE2 ectodomain and downregulation of the enzyme upon interaction with the virus add even more layers of reciprocal complexity to the ACE2 and SARS-CoV2 relationship [149e151]. Moreover, it has been reported that distinct clinical outcomes of SARS-CoV-2 infection may depend on the correlations of ACE2 expression with immune signature enrichment levels of patients [152]. However, the detailed elements in the host system regulating ACE2 expression in COVID-19, especially at the gene production level, remain unclear. The genetic variability of the ACE2 gene is currently under investigation in regard to the effect of certain polymorphic alleles on the course and outcome of COVID-19 [153]. Functional polymorphisms impose structural changes in the final protein product of this enzyme [153], which affects the interactions of ACE2 with the spike glycoprotein on the surface of the SARS-CoV-2 viral strain [154e156]. The G8790A variation rs2285666 is a key functional polymorphism of the ACE2 gene. The A polymorphic allele causes up to a 50% increase in gene expression of ACE2 when in homozygosity in comparison with the G allele [157,158]. The GG genotype G8790A polymorphism is associated with an almost

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twofold increased SARS-CoV-2 infection risk and a threefold increased risk to develop serious disease or COVID-19 fatality [159]. In contrast, the A allele in this variation, which is characterized by enhanced gene expression and enzyme activity of ACE2, has been associated with decreased risk of infection and COVID-19related death [160]. The rs5934250 is another functional ACE2 polymorphic variant that decreases the expression [153], whereas the polymorphisms rs182366225 and rs2097723 can increase ACE2 gene expression [161]. Other polymorphisms in ACE2 gene associated with an increased predisposition to viral infection including COVID-19 are rs4646114 and rs4646115, as opposed to rs536092258 and rs370596467, which provide a favorable response to infection [162]. Collectively, ACE2 polymorphism is an important mechanism that underlies the SARS-CoV-2 infection and the severity and mortality of COVID-19 [153,159]. Moreover, the frequency of certain ACE2 gene variants is altered in different populations, which can be a possible indicator for the epidemiological status of COVID-19 in the different countries or continents [153,163,164].

9. Role of ACE2 in lung repair and regeneration The ultimately healing in injured lung requires inflammation resolution [165]. Recently, ACE2 is indicated as a driver to facilitate inflammation resolution [165]. The protective effects of ACE2 in the models of lung pathologies, as discussed in the previous sections, are mainly attributed to the immunomodulatory properties of this signaling. The antiinflammatory actions of ACE2 could reduce tissue damage and promote repair in lung. Moreover, the antifibrotic effects of ACE2 indicate the proregenerative activities of this enzyme in the healing process of injured lung. This was supported by the findings that ACE2 deficiency exaggerated bleomycin-induced fibrosis [69] and ACE2 activation reversed the vascular remodeling in rodent PH models [28,166]. The regulation of pulmonary stem/progenitor cells by ACE2 is a key mechanism that underlies the ACE2-facilitated lung regeneration. Lung repair and regeneration are complex and conditional. Basal cells, Clara cells, type II pneumocytes, and the putative pulmonary stem/progenitor cells are proposed to contribute to lung repair and regeneration in response to lung injury [167e169]. These cells are characterized as CD34þ/Sca-1þ/CD45
/PE-CAM
, localized at the bronchoalveolar duct junction of adult lungs, and are termed as bronchoalveolar stem cells (BASCs) [170]. In addition, Oct-4, which is critical to maintain pluripotency in embryonic cells, is expressed in the cells at the bronchoalveolar junction of the neonatal lung [171]. The BASCs were identified as a subset of Oct4þ ACE2þ epithelial colony cells. ACE2 expression in these BASCs was regulated by miR-223 and miR-98 [172], which accounts for the capacity of these epithelial stem/progenitor cells for lung repair [172]. ACE2 also governs the function of endothelial progenitor cells (EPCs) via eNOS and NADPH oxidase (Nox) pathways and thereby enhances the therapeutic efficacy of EPCs for tissue injury [173], suggesting

9. Role of ACE2 in lung repair and regeneration

the ACE2-potentiated pulmonary vascular endothelial regeneration. ACE2 also regulates MSCs for lung repair and regeneration. ACE2 overexpression (lentiviral transfection) in human umbilical cord MSCs ameliorated the bleomycin-induced mouse lung fibrosis [75]. ACE2-overexpressing mouse bone marrow MSCs mitigated the LPS-triggered lung inflammation and injury in vivo [174]. ACE2 activation in MSCs rescued the LPS-induced dysfunction of lung ECs [118] and mammary epithelial cells [175] in vitro. Moreover, ACE2 facilitated human umbilical cord MSCs to heal the ischemia reperfusion (I/R)einduced lung injury [176,177]. Mechanistically, ACE2 in MSCs attenuated the I/R-induced DNA damage and inflammatory/fibrotic responses in lung [176,177]. In this I/R-induced lung injury model, MSCs harboring ACE2 also promoted proangiogenic and antioxidant actions [176,177]. Human studies revealed that ACE2 is notably expressed in SOX9positive lung progenitor cells detected in both pluripotent stem cell derivatives and infants’ lungs [178,179], further suggesting a role of ACE2 signaling in lung development, regeneration, and plasticity. Interestingly, it has been observed in human and mouse models that smoking (including electronic cigarette, with or without nicotine) [105,180] induced upregulation of ACE2 in lung, which was mediated by the nAChRa7 receptor [105]. In the lung of these smokers, ACE2 was linked to the dysregulated repair and extracellular matrix (ECM) remodeling, as well as to the fibroblast migration to injured lungs [105]. Further studies are required to elucidate the detailed role of ACE2 signaling in the complex biological processes of lung repair and regeneration. Nevertheless, the proregenerative activities of ACE2 indicate that the recombinant proteins, activators, and enhancers of ACE2 have potential therapeutic value to prevent and treat a variety of lung inflammation-related pathologies including PH, asthma, fibrosis, cancer, COPD, and ALI (Fig. 10.3 and Table 10.1).

FIGURE 10.3 The immunoregulatory role of ACE2 in the pulmonary diseases.

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Table 10.1 Summary of roles of ACE2 in lung diseases.

Pulmonary hypertension

Outcomes of ACE2 activation or overexpression

Factors/drugs that regulate ACE2 in the disease development

Proinflammatory cytokines Oxidative stress

Hemodynamics (RVSP) RV hypertrophy (RV/ LV þ S)

Profibrotic cytokines (TGF-b1) Ang II/AT1R activity

Vascular remodeling EC dysfunction

SU5416/ hypoxiadmouse

JAK/STAT

PV-SMC apoptosis

AMPKdenhances ACE2 stability MSC-derived microvesiclesdactivate ACE2 HIF-1a-MiRNA let7bdinhibits ACE2 Other drugs: magnolol and fasudildactivate ACE2 rhACE2 (GSK2586881, clinical trial)dupregulates ACE2

MCT þ left pneumonectomdrat Chronic cigarettedrat Ascending aortic bandingdmouse SU5416 þ left pneumonectomdrat Idiopathic PAHdhuman SSC PAHdhuman CHD PAHdhuman

eNOS Ser1177 phosphorylation eNOS Thr495 dephosphorylation FAO

PV-SMC migration

Study models/ subjects Monocrotaline (MCT)drat MCTdmouse

Chronic hypoxiadrat Bleomycindrat

ACE2 alterations Expression Activity

Expression (compensational?)

Hippo/LATS1/Yap pathway PSD-2

PV-SMC proliferation Balance of brainegut elung axis Bone marrow ederived EPCs

CHAPTER 10 ACE2 in pulmonary diseases

Setting

Molecular mechanisms (regulated by ACE2 activation/ overexpression)

Asthma

Expression (in Th2high asthma)

IL-5, IL-13 and IL-33

Airway hyperresponsiveness

OVAdrat

Expression (in Th2low asthma)

IL-1b, IL-4, NF-kB, BCL2, p-AKT and pp38

Airway inflammation

Th2-high endotypedhuman

Activity

Ang II/AT1R activity

Airway remodeling

Th2-low endotypedhuman

Ang-(1e7)/Mas1R activity

RV hypertrophy

Bleomycindmouse

Expression

sACE2 and ADAM17 TGF-b1, a-SMA, bP4H, MMP-1, and MMP-2

Bleomycindrat

Activity

NOX4/ROS/RhoA/ Rock pathway

Myofibroblast differentiation

Silicadrat

Expression (dynamic variation?)

Ang II/AT1R activity

Lung fibroblast migration

Ang-(1e7)/Mas1R activity

Lung epithelial injury (apoptosis)

Bleomycin þ PMmouse

Collagen I synthesis and deposition

Th2 (IL-4, IL-13) cytolkinesddownregulate ACE2 (in Th2-high asthma) Th1/Th17 (TNF, IL-12, IL17A, IL-8, IL-19, IFNs) cytokinesdupregulate ACE2 (in Th2-low asthma) Male sex, African American race, and history of diabetes mellitusdassociated with ACE2 upregulation Short-term ICSsddownregulates, whereas long-term ICS treatmentdupregulates ACE2

Tanshinone IIA and osthole (Chinese herbal extracts)dupregulate ACE2 The peptide AcSDKPddownregulates ACE2 JNKdupregulates ACE2

KC(IL-8)/CXCR1/2 signalingdupregulates ACE2 Continued

9. Role of ACE2 in lung repair and regeneration

Pulmonary fibrosis

HDMdmouse

299

300

Setting

Study models/ subjects

ACE2 alterations

IPFdhuman

Lung cancer

Outcomes of ACE2 activation or overexpression

MAPK/NF-kB pathway

Lung fibroblast proliferation Leukocyte infiltration Lung tumor cell growth

NSCLCdhuman

Expression (in NSCLC)

VEGF

LUADdhuman

Activity (in A549 cells) Expression (in NSCLC, LUAD, LUSC, SCLC)

MMP-2 and MMP-9

LUSCdhuman

SCLCdhuman

COPD

Molecular mechanisms (regulated by ACE2 activation/ overexpression)

A549 tumor tissue xenograftsdmouse COPDdrat

PM1drat

Ang II/AT1R activity

Lung tumor cell migration Tumoral angiogenesis

HHIP, CD36, and DMBT1 (associated)

Lung tumor cell viability

Expression (in COPD rats)

MDA, ROS and 8isoprostane (oxidative stress)

Lung function

Expression (in smokers and COPD patients)

TNF-a; IL-2, IL-6, and IL-1b (proinflammation)

Emphysema

Factors/drugs that regulate ACE2 in the disease development

WT1, STAT3, YY1, AREB6, ERG, GKLF, GATA2 (TFs)dupregulate ACE2 miR-181bdupregulates ACE2

Smoking (tranditinal/ electronic cigarette, w/o nicotine)dupregulates ACE2 Overweightdasscoaited with ACE2 upregulation

CHAPTER 10 ACE2 in pulmonary diseases

Table 10.1 Summary of roles of ACE2 in lung diseases.dcont’d

sACE2 level (in COPD patients)

NF-kB and p38 MAPK

Lung inflammation

Miz1 (suppressor of NFkB)ddownregulates ACE2

Lung epithelial deletion of Miz1 (POZ)dmouse

Expression (in SPCCreþ/ Miz1(POZ)fl/fl mice)

Caspase-3

Chronic bronchitis

Type I IFNsdupregulate ACE2

Endotoxin (LPS)dmouse Sepsisdmouse

Expression

ROS

Shedding

Ang II/AT1R activity

Acid aspiration

Activity

Ang-(1e7)/Mas1R activity

Virus docking (SARSCoV) Edema, vascular permeability Inflammatory cell infiltration

Limb ischemiareperfusiondmouse PM2.5dmouse

p-STAT3 and pERK1/2 DABK/BKB1R

Lung EC dysfunction Lung EC viability

LPS—human PMVECs

NF-kB, TLR4

Lung function

Bleomycindmouse

CXCL5, MIP2, and KC (chemokines)

Acid aspiration pneumonia

Endocytic pathways (lysosomes and endosomes)dasscoaited with ACE2 upregulation The RNA-binding protein HuRdupregulate ACE2 LPSddownregulates ACE2 Lipoxin A4dactivates ACE2 Chinese herbal extract sini decoctiondupregulates ACE2 Glycyrrhizic acid (HMGB1 inhibitor)—activates ACE2 SARS-CoV spike proteinddownregulates ACE2 SARSCoV2ddownregulates ACE2

Continued

9. Role of ACE2 in lung repair and regeneration

ALI

COPDdhuman

301

302

Setting

COVID-19

Study models/ subjects

ACE2 alterations

Molecular mechanisms (regulated by ACE2 activation/ overexpression)

SARS-CoV spike proteindmouse

VEGF and PLGF

Viruses (SARS-CoVs, H1N1, H5N1, H7N9)dhuman

(Proinflammatory) TNF-a and IL-1b

SARS CoV2-human

Expression

Shedding

(Antiinflamamtory) IL-10 MAPK and Notch (corelated) Rnf128, Muc5b, and Tmprss2 (coexpressed) Production of cytokines (cytokine storm)

Outcomes of ACE2 activation or overexpression

Factors/drugs that regulate ACE2 in the disease development

Viral entry and infectivity

TMPRSS2 downregulates ACE2 (by cleaving)

Inflammation

ADAM-17 downregulates ACE2 (by cleaving) SARS-CoV2 downregulates ACE2 (by shedding)

Possible pulmonary fibrosis

CHAPTER 10 ACE2 in pulmonary diseases

Table 10.1 Summary of roles of ACE2 in lung diseases.dcont’d

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Renineangiotensine aldosterone system inhibitors. New and old approaches

11

Carlos M. Ferrario, Jessica L. VonCannon, Kendra N. Wright, Sarfaraz Ahmad Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, United States

1. Introduction From 1990 to 2019, the number of people aged 30e79 years worldwide with hypertension doubled [1]. High blood pressure is responsible for 8.5 million global deaths from stroke, ischemic heart disease, and renal disease [2]. Benefits achieved by controlling high blood pressure in terms of total cardiovascular health are widely acknowledged by physicians and healthcare professionals. Contemporary clinical studies and metaanalysis, driven by the impressive outcomes of intensive blood pressure control in the Systolic Blood Pressure Intervention Trial (SPRINT) [3], favor targeting antihypertensive therapy to attain a blood pressure
130/80 mm Hg [4e8]. Intense blood pressure control for these newer targets requires the combination of two or more antihypertensive drugs, which, even when compounded into a single formulation, impact long-term therapeutic adherence [9]. While spending on medicines continues to grow at a fast pace, most of the spending growth will occur in the fields of immunology, oncology, and neurology [10]. For the most part, established pharmaceutical companies are disinclined to commit resources to the development of new classes of antihypertensive therapies. The tenet that the antihypertensive market is saturated with safe antihypertensive drugs ignores the limited benefit of current therapies in halting the progression of cardiovascular events and all-cause mortality [11e15]. Opinion leaders with conflicting interests [16], and the current donorerecipient types of interaction existing among pharmaceutical companies, professional societies, and healthcare providers [17], contribute to the existence of an environment less inclined to recognize a critical need for a renewed vigorous effort to develop new antihypertensive therapies. Against the viewpoint of current opinion leaders, Dzau and Balatba [18], Azizi et al. [19], and Ferrario and collaborators [13,14] have challenged the current apathy to identify new targets for hypertension drug development. Pharmacological strategies demonstrating the most effective achievement of blood pressure control, overt cardiac, vascular, and renal organ damage, cardiovascular morbidity, and mortality are attainable with prescriptions that interfere with the Angiotensin. https://doi.org/10.1016/B978-0-323-99618-1.00013-1 Copyright © 2023 Elsevier Inc. All rights reserved.

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actions of the renineangiotensinealdosterone system (RAAS). Medications that interfere with the RAAS include [1] angiotensin-converting enzyme (ACE) inhibitors [2]; angiotensin II (Ang II) type I receptor (AT1-R) blockers (ARBs) [3]; direct renin inhibitors (DRIs); and [4] mineralocorticoid receptor antagonists [13]. We mention in this discussion vasopeptidase inhibitors, a new class of medications that simultaneously inhibit both neprilysin (neutral endopeptidase 24.11) and ACE [20e23] or the neprilysin inhibitor sacubitril combined with the ARB valsartan [24].

2. Why new drugs for hypertension Pioneer efforts to toning-down the actions of Ang II in the control of high blood pressure led to the isolation and synthesis of peptide inhibitors of ACE [25,26]. In a landmark study by Gavras et al. [27], the nonapeptide ACE inhibitor (SQ 20,881) produced an immediate antihypertensive response in 23 hypertensive patients that was sustained for up to 16 h after its injection. The evolution of this proof of concept to the modern pharmacotherapy of cardiovascular diseases and diabetes mellitus by way of orally active direct renin and ACE inhibitors and ARBs has become the pillar of all contemporaneous therapeutic plans and international medical guidelines [28,29]. Despite their proven benefits, their therapeutic usefulness has several limitations related to efficacy, the need for polypharmacy, and side effects. Furthermore, the effectiveness of renineangiotensin system inhibitors in preventing hard clinical endpoints such as strokes, myocardial infarction, atrial fibrillation, and progression of diabetic nephropathy is limited when outcomes from landmark clinical trials are evaluated in terms of either the absolute risk reduction or the residual risk. As clearly remarked by The Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC), “risk-based treatment has been a cornerstone of lipid management for a decade” [30]. Therefore, it is worth reviewing the meaning of these two treatment outcome indicators because hypertension practitioners and clinical investigators often ignore them in judging the true benefits of an intervention. The absolute cardiovascular risk defines the actual success of an intervention in terms of the number of people experiencing an event relative to the population at large. On the other hand, the residual cardiovascular risk measures the remaining risk of cardiovascular events persisting in patients treated with current evidencebased care. A 2014 BPLTTC report of the absolute risk reduction of blood pressuree lowering drugs from 11 published trials revealed an abysmal failure of hypertension treatment as no more than 38 cardiovascular events could be prevented by treating 1000 patients over 5 years [30]. A comprehensive analysis of the efficacy of ACE inhibitors and ARBs on mortality by van Vark et al. [31] documented a significant 5% reduction in all-cause mortality (HR: 0.95, 95% CI: 0.91e1.00, P ¼ 0.032) and 7% reduction in cardiovascular mortality (HR: 0.93, 95% CI: 0.88e0.99, P ¼ 0.018) in a metaanalysis of 20 trials employing ACE inhibitors or ARBs. From these data, it can be determined that the residual risk for all-cause and cardiovascular mortality averaged 95% and 93%, respectively. These findings agree with studies by Ferrario

2. Why new drugs for hypertension

and colleagues [13,14]. Therefore, it may be concluded that organ-protective effects of ACE inhibitors and ARBs are limited as cardiovascular mortality and decline in renal function remain high [12]. The predisposing impact of hypertensive vascular disease to cardiovascular disease and premature death justifies seeking to augment the efficacy of RAAS blockade by redesigning current ACE inhibitors and ARBs to augment their access to intracellular sites, exploring the efficacy of suppressing the activity of alternate angiotensins forming enzymes, and refining the potential utilization of gene and immunological-based approaches to suppress Ang II pathological actions.

2.1 Renin The first extensive purification of renin was done by Hass et al. [32], while the isolation of pure renin from hog and human kidneys [33e35] facilitated Murakami and associates [36,37] description of the molecular structure of the renin gene. Early recognition of renin immunogenicity prompted Haber’s conceptualization of inhibiting renin from preventing Ang II production. As a chief advocate of manipulating renin to interfere with its Ang II-forming mechanisms, Haber visualized three classes of compounds: specific antibodies, acid protease inhibitors, and substrate analogs [38]. In championing an immunological approach, Haber and his disciple Dzau focused on exploring renin-specific antibodies, and Fab fragments (the fragment antigen-binding region) in dogs exposed to sodium depletion or acute renal artery constriction [39]. Their efforts in the 1980s included the description of the specificity of renin monoclonal antibodies (mAb) as tools for physiologic studies in subhuman primates and man [40,41]. This line of approach was abandoned in favor of exploring the utility of chemical renin inhibitors [42e44]. The reactive increase in plasma renin activity in response to inhibition of Ang II production or activity with ACE inhibitors or ARBs gave impetus to the introduction by Novartis, Inc. of aliskiren fumarate as the first effective orally active renin inhibitor [45]. In several short-term clinical trials, aliskiren demonstrated significant efficacy as monotherapy or in combination with ACE inhibitors, ARBs, thiazide diuretics, and calcium channel blockers [46,47]. Aliskiren inclusion in the pharmacotherapy of hypertension, cardiac, and renal disease has been neglected because of concerns regarding worsening of renal function, hypotension, and hyperkalemia when combined with other antihypertensive agents. The absence of long-term outcome studies and a preliminary report of a slight excess of cardiovascular events (death or stroke) in the aliskiren group in the ALTITUDE trial militated against its use [48,49]. Furthermore, the potential for renin inhibition to be harmful was recently suggested by the occurrence of concentric thickening of the intrarenal arteries and arterioles in mice following the deletion of the renin gene [50]. Their findings in mice are in keeping with the demonstration of worsening of the renal parenchymal disease and increased peritubular fibrosis by combined chronic treatment with aliskiren and valsartan in transgenic renin-dependent hypertensive rats [51].

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2.1.1 Angiotensinogen In one of the most comprehensive descriptions of the plasma substrate forming Ang II, Skeggs [52] first elaborated on the efforts expended in documenting the “existence or efficacy of inhibitors or activators of the reaction.” In discussing ways to inhibit renin, Page [53] mentions that Haber had predicted that the AGT molecule might be considered a potential renin inhibitor. Evidence favoring this possibility was surprisingly circumscribed to des[Ang I]AGT, the larger fragment of the AGT molecule [54,55]. The fact that the amino acid composition of the substrate from different species varies markedly in terms of their susceptibility to hydrolysis by heterologous renin may be behind their past approach. Newer tactics to evaluate the potential therapeutic response of AGT inhibition in hypertension entail silencing the AGT gene or employing antisense oligonucleotides (ASOs) [56]. The feasibility of silencing the AGT gene had been explored previously in 3T3-L1 adipocytes using vector-based short hairpin RNA (shRNA), a type of RNA interference (RNAi) technology [57]. A year later, Olearczyk and colleagues at Merck Sharp and Dohme Corp [58], reported the successful suppression of hepatic AGT in SD and SHR rats using small interfering RNAs (siRNAs) targeting hepatic AGT. Further progress was attained by Dutch investigators [59] who showed a modest 4-week sustained blood pressureelowering effect in SHR by receiving fortnight subcutaneous injections of an AGT small interfering RNA (siRNA). The fall in the blood pressure produced by the injection of the AGT siRNA was markedly potentiated by concomitant administration of captopril or valsartan [59]. Additional support for the introduction of novel therapies based on silencing the AGT is derived from the observation of reduced proteinuria, glomerulosclerosis, and cardiac hypertrophy in a rat model of chronic kidney disease accomplished by 5/6th nephrectomy [60]. The specificity of inhibiting hepatic AGT synthesis from preventing Ang II pathological actions is buttressed in an experiment employing DOCA-salt hypertensive rats [61]. In this study, suppression of circulating AGT with a siRNA failed to lower the elevated blood pressure of salt-dependent hypertension, an experimental model resistant to the antihypertensive effects of ARBs [62]. The effectiveness of silencing the AGT gene as a novel hypertension therapy has been validated by Alnylam Pharmaceuticals Inc. (Cambridge, MA), a biopharmaceutical company focused on the discovery, development, and commercialization of RNA interference therapeutics for genetically defined diseases. Interim results from a 12week Phase I study of ALN-AGT01 (Zilebesiran) in 60 untreated hypertensive patients (SBP >130 mm Hg and
165 mm Hg) receiving single ascending doses of the AGT siRNA (10e200 mg, s.c.) were presented at the annual AHA National Meeting in 2020 [63]. A 95  2% mean reduction in serum AGT at 8 weeks (200 mg dose) was associated with a decrease in arterial pressure averaging 11  2/8  1 mm Hg [63]. A more significant and sustained 24 h antihypertensive response (22  2.9/-14.3  2.3 mm Hg) was obtained following a single dose of 800 mg s.c. of Zilebesiran on day 41 [64]. In addition, coadministration of irbesartan (300 mg PO) for an additional 2 weeks enhanced the blood pressure response.

2. Why new drugs for hypertension

Altogether, these data suggest that Zilebesiran is well tolerated in patients with hypertension with no adverse hypotension or clinically significant laboratory abnormalities [65]. A phase II randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of Zilebesiran when used in combination with conventional antihypertensive medications is in progress (KARDIA-2; https://clinicaltrials.gov/ct2/ show/NCT05103332). The trial seeks to evaluate the efficacy and safety of Zilebesiran as concomitant therapy in adults whose blood pressure is not adequately controlled by antihypertensive medications (ACE inhibitor, ARB, renin inhibitor, calcium channel blocker, thiazide diuretic, and/or thiazide-like diuretic). ASO that inhibits AGT RNA translation is another strategy that has now reached clinical relevance. Pioneered by IONIS Pharmaceuticals (Carlsbad, CA), IONISAGT-LRx ASO is covalently linked to becoming a high-affinity ligand for the hepatocyte-specific asialoglycoprotein receptor [66,67]. Conjugation to this ligand (triantennary N-acetylgalactosamine) increases the potency of ASO by as much as 30-fold [68]. Results from phase I and phase II clinical trials, as summarized by Morgan et al. [69], documented favorable effects in terms of reducing plasma AGT, excellent tolerability with no hypotensive responses or induction of hyperkalemia [69]. The data reviewed in Morgan et al. [69] suggest a numerically variable but promising effect on blood pressure. The efficacy of IONIS-AGT-LRx is being pursued in three currently registered clinical trials (NCT04714320, NCT04836182, and NCT04731623 [69]). The relative superiority of AGT suppression by either silencing the AGT gene or administration of ASO remains to be determined. Critical arguments for each approach are summarized in a recent publication [56]. In our opinion, the antihypertensive response induced by the ASO in spontaneously hypertensive rats (SHR) fed a high-salt diet [68] is an intriguing positive response not duplicated in DOCA-salt rats medicated with Zilebesiran [70]. Beneficial effects of the suppression of RAS may be overcome by excessive elimination of Ang II in terms of renal function preservation. This possibility gains support in experiments in which the combined administration of aliskiren and valsartan induced marked worsening of renal parenchymal disease despite improved blood pressure, reversal of cardiac hypertrophy, and proteinuria [51]. Watanabe et al. [50] recently expanded on this possibility by showing that long-term inhibition of RAS leads to concentric thickening of the intrarenal arteries and arterioles in both mice and humans. It is generally thought that AGT serves solely as the substrate for the metabolic processing of the protein by renin. The fact that the amino acids coding for the angiotensins comprise the first 33 amino acids of the 245 amino acids in the human AGT protein assumes that the remaining >97% of the protein codes for no additional functions. Ferrario and colleagues [71] have expressed concerns on this viewpoint by reviving the solid work of others who showed that des-(Ang I)-AGT possesses antiangiogenic actions [72], inhibits vascular endothelial growth factor cell migration [73], and modulates bloodebrain barrier permeability [74,75] and hepatic steatosis [76,77]. The consequences of long-term inhibition of AGT remain to be investigated.

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An alternate approach to suppressing the hepatic expression of the AGT protein arises from the identification of a shorter fragment of the AGT molecule, originally named proangiotensin-12 [78]. As illustrated in Fig. 11.1, proangiotensin-12 (heretofore renamed as angiotensin-(1e12) [81]) is composed of the first 12 amino acids of the AGT protein [81]. This Ang II-forming substrate circulates in the blood of rodents [82] and humans [83,84] and is expressed in human [85e88] and rodent hearts [89e93], the adrenal glands [78,94,95], the rat small intestine [78,94,95], the rodent kidney and human urine [83,90], the rat bone marrow, and the rat’s thymus [81,96]. The importance of Ang-(1e12) as a circulating and tissue source of Ang II production has been extensively reviewed elsewhere [81,97,98]. Two critical studies are underscored. First, Ferrario et al. [84] found high plasma levels of Ang-(1e12) in untreated primary hypertensive patients. Second, in a parallel study, successful control of blood pressure with antihypertensive medications was associated with lower plasma Ang-(1e12) concentrations compared with the plasma values recorded in patients in whom blood pressure remained uncontrolled despite medications [83]. The potential for Ang-(1e12) as a source of increased production of tissue Ang II by chymase was demonstrated by a study in which human right and left atrial tissue was obtained during open-heart surgery [87,88]. The maladaptive left atrial and ventricular remodeling in response to resistant atrial fibrillation and left heart disease was accompanied by augmented values of chymase gene transcripts and increased

FIGURE 11.1 Schematic representation of angiotensinogen (AGT) leading cleaved derivatives by renin: angiotensin-(1e10) (Ang I) and the residual protein des-(Ang I)AGT comprised of the remaining 442 amino acids of no known function until Celerier et al. original report [79]. Single-letter amino acid names [80] denote the main human AGT cleaved products yielding the generation of Ang I (Ang-(1e10)), angiotensin-(1e12) (Ang-(1e12)), and angiotensin-(1e25) (Ang-(1e25)) from the AGT N-terminus.

2. Why new drugs for hypertension

content of Ang-(1e12) [87,88]. These recent findings corroborated our early demonstration [85] of high chymase activity and chymase-dependent Ang-(1e12) metabolism in the left atrial appendage of patients who underwent the COX-MAZE procedure [99] to eliminate atrial fibrillation. The potential therapeutic advantages of Ang-(1e12) neutralization in the treatment of cardiovascular disease remain to be determined. Steps toward the achievement of this objective in our laboratory are currently in progress. Extending the demonstration of antihypertensive effects produced by endogenous brain Ang(1e12) neutralization [100], administration of a monoclonal antibody (mAb) against the human sequence of Ang-(1e12) elicited an antihypertensive response in rats expressing the human AGT gene in their genome [101]. If proven successful in longer-term studies, mAbs against Ang-(1e12) may obviate the potential adverse effects of the complete elimination of the AGT protein.

2.1.2 Blocking the activity of the ACE/Ang II/AT1-R Among the several established antihypertensive drug classes, ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists remain the recognized drivers to counteract the excess activity of the RAS. A robust literature documented their effectiveness and limitations [13,18,56,102,103]. The publication of the SPRINT Trial [3] and increased awareness of the limited efficacy in reducing cardiovascular events with the use of ACE inhibitors and ARBs [11,30,104e106] underscored a need to explore better and more specific therapeutic strategies for achieving greater blood control and enhanced patients’ adherence to medications. While fixed-dose combination pills allow for improved blood pressure control [102], persistence in therapy remains a significant obstacle [107]. Therapeutic efforts to increase the efficacy of RAS blockade include the introduction of new ARBs (Allisartan and Fimasartan) [102] and the mineralocorticoid receptor (MR) antagonist finerenone [108]. A fixed-dose combination of a neprilysin inhibitor (sacubitril) and the ARB valsartan was introduced in 2014 for the treatment of heart failure [24,109e111]. The antihypertensive effects of this fixed-dose combination have been evaluated in multiple studies, particularly in patients with resistant hypertension [102,112e115]. While results have been encouraging, the absence of long-term studies in terms of reversal of target organ damage, adverse events, and comparative results are obstacles to an FDA approval of this combination therapy to treat high blood pressure. The successes achieved by implementing novel molecular approaches to vaccine development in addressing the SARS-CoV-2 mediated pandemic will stimulate the further development of vaccines to manage noncommunicable diseases. As commented by Azegami and Itoh [116], the idea of employing immunotherapies to control blood pressure in hypertension was attempted 81 years ago. In that study, Page et al. [117] reported an antihypertensive effect of kidney extracts in patients. Vaccines directed against the RAS peptides and receptors continue to be explored as alternate approaches to suppress excess Ang II overactivity. The potential for long-term therapeutic benefit and low frequency of administration addresses behavioral issues of

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lifelong treatment with drugs. Currently, vaccines utility is investigated for the treatment of high blood pressure [118,119], obesity [120], and type 2 diabetes [121,122]. As reviewed elsewhere [98,123,124], vaccines directed against renin [125,126], Ang I [127,128], and Ang II [119] have met with relative success. While immunoneutralization against renin and Ang I was effective in reducing the blood pressure in experimental animals, effective translation to humans has been precluded by activation of immunological responses to the antigens [125]. Newer procedures addressing the immune tolerance against self-antigens are in progress [116,129]. The status of this field is well summarized elsewhere [98,130,131]. Clinical trials with the Ang II vaccine─AngQb-Cyt006─have met with moderate success [119,132]. Other ongoing clinical trials are documented elsewhere [98].

2.1.3 Potentiating the opposing function of the ACE2/Ang-(1e7)/Mas-R axis Ferrario’s laboratory discovery of angiotensin-(1e7) (Ang-(1e7) as a counterregulator of the pressor and proliferative Ang II actions [22,133e138] and the later demonstration of angiotensin-converting enzyme 2 (ACE2) in hydrolyzing Ang II into Ang-(1e7) [139,140] led to exploring the development of drugs limiting Ang II-overactivity through enhancement of the ACE2/Ang-(1e7)/Mas-R axis. The rationale for this approach was cemented by the demonstration of lower excretion rates of Ang-(1e7) in primary hypertension [141]. The urinary Ang-(1e7) content, reflecting the activity of the RAS in the kidney, was enhanced in patients medicated with captopril [142] or omapatrilat, a dual inhibitor of neprilysin and ACE [23]. The potential for using Ang-(1e7) as a therapeutic agent is based on the reported success of preclinical studies using hydroxypropyl-b-cyclodextrin/Ang-(1e7)] [143e145] and cyclic Ang-(1e7) [146]. Blood Ang-(1e7) rapid degradation into Ang-(1e5) by ACE has limited its therapeutic potential [147]. This limitation is addressed in newer formulations [HPbCD/Ang-(1e7) [148], NorLeu3-Ang-(1e7) [149,150], AVE-0991 [151], and a Mas receptor agonist CGEN-856 [152]. The key role that ACE2 plays in the conversion of Ang II into Ang-(1e7) [153] is the basis for interrogating the potential effectiveness of recombinant human ACE2 (rhACE2) as a therapeutic agent for the treatment of SARS-CoV-2 coronavirus infectiveness [154,155]. A current summary of results obtained in the treatment of COVID-19 is documented elsewhere [56]. Two other clinical studies with rhACE2 in healthy volunteers [156] and pulmonary hypertensive patients [157] are currently in progress.

3. Perspective Primary hypertension is a critical contributor to the adverse cardiovascular and renal adaptation that leads to myocardial failure, cerebrovascular disease, cognitive impairment, and chronic renal disease. A clear and convincing rationale for aggressive blood pressure control is established. Yet, available medicines are only partially

References

effective in controlling blood pressure. Moreover, management of hypertension signifies a lifetime commitment to drug therapy with consequences such as poor adherence to medications and financial stress. Exploring new therapeutic avenues that require less than daily use of medications and increased 24 h blood pressure control is an emerging field; it is hoped that these new molecular and immunological approaches may be more effective alone or in combination with current antihypertensive medications.

Acknowledgments Work in the authors’ laboratory is supported by funding from the National Heart, Lung, and Blood Institute (HL-051952) and the National Aging Institute (1 R21 AG070371-01) of the National Institutes of Health (NIH). The authors declare no conflicts of interest.

References [1] Collaboration NRF. Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 populationrepresentative studies with 104 million participants. Lancet (London, England) 2021;398(10304):957e80. [2] Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics-2019 update: a report from the American heart association. Circulation 2019;139(10):e56e528. [3] Sprint Research Group, Wright Jr JT, Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373(22):2103e16. [4] Carey RM. 2018 American Heart Association redefinition of resistant hypertension: major adverse cardiovascular and renal events. J Clin Hypertens 2020;22(11):2103e4. [5] Carey RM, Whelton PK. Evidence for the universal blood pressure goal of > AT2 or Mas) that favor an increase in cellular oxidative stress [30]. Apart from the nucleus, the mitochondria may constitute another key intracellular site for both the classical and nonclassical RAS [5,9e11]. Previous studies by Ferder and colleagues, as well as Doughan et al demonstrate an important role

2. Kidney

FIGURE 12.4 Ang-(1e7) Stimulates Nitric Oxide in Isolated Renal Nuclei from Sheep. (A) Ang-(1e7) potently stimulates nitric oxide (NO) assessed by the increase in DAF as com pared with Ang II in isolated renal cortical nuclei. (B) The nuclear NO response to Ang-(1e7) is abolished by the Mas receptor antagonist [D-Ala7]eAng-(1e7) (DALA) and NO synthase inhibitor LNAME, but not the AT1R antagonist losartan (LOS) or the AT2R antagonist PD12 3319 (PD). (C) Ang II stimulates ROS (increase in DCF fluorescence) in isolated cortical nuclei that are blocked by LOS, but not PD. DALA and the ACE2 inhibitor MLN4760 sign ificantly enhanced the Ang II ROS response. (D) Renal cortical nuclei process Ang II to Ang(1e7) which is abolished by the ACE2 inhibitor MLN as revealed by reverse-phase highperformance liquid chromatography (RP-HPLC). Data adapted from the following: Gwathmey T.M. et al., Angiotensin-(1e7)-ACE2 attenuates reactive oxygen species formation to angiotensin II within the cell nucleus. Hypertension 2010; 55: 166e171; Gwathmey T.M. et al., Glucocorticoid-induced fetal programming alters the functional complement of angiotensin receptor subtypes within the kidney. Hypertension 2011; 57: 620e626; Gwathmey T.M. et al., Nuclear angiotensin(1e7) receptor is functionally coupled to the formation of nitric oxide. Am J Physiol Renal Physiol 2010; 299: F983eF990.

of extracellular Ang II in the functional health of the mitochondria [36e38]. Abadir et al. [39] subsequently found that isolated mitochondria from murine proximal tubules and other tissues expressed the AT2 receptor protein to a greater extent (40-fold) than the cell surface receptor. The stimulation of the mitochondrial AT2 receptor was associated with an increase in NO levels and a reduction in overall mitochondrial respiration suggesting a protective effect of the AT2 receptor [39].

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Micakovic et al. [40] demonstrated both AT1 and AT2 receptors by 125I-[Sar1, Ile8]Ang II binding in isolated mitochondrial from the rat kidney using selective antagonists, but a greater predominance of AT1 receptors in the mitochondria of older rats. In the Micakovic study [40], the overexpression of the AT2 receptor attenuated renal injury in rats made diabetic by streptozotocin, a response that was associated with improved mitochondrial function. Wilson et al. [41] provided initial evidence that mitochondria isolated from the sheep renal cortex contain an Ang-(1e7)-Mas receptor system. The Wilson study [41] demonstrated mitochondrial expression of the Mas receptor protein, the peptidases neprilysin and thimet oligopeptidase that converted Ang I directly to Ang-(1e7), protein levels of angiotensinogen and active renin, as well as peptide levels of Ang-(1e7), Ang II, and Ang I (see Section 5). Zhuo and colleagues [42] have also addressed the role of mitochondrial AT1 receptors within the kidney by constructing an Ang II vector with a mitochondrial localization sequence that preferentially targets the peptide to mitochondria. Intracellular expression of mitochondrial Ang II in mouse proximal tubule cells increased both mitochondrial oxidative stress (OCR) and glycolysis stress (ECAR), which were associated with increased expression of the MAP kinase phospho-ERK1/2, phospho-NHE3, and the Naþ,Kþ-ATPase, but no change in the Naþ/HCO3 transporter [42]. The cellular effects of mitochondrial Ang II were attenuated by extracellular treatment with losartan that suggests this antagonist can effectively target the intracellular mitochondrial AT1 receptor [42]. Surprisingly, extracellular treatment with the AT2 receptor antagonist PD123319 had a comparable inhibitory effect to losartan; however, whether these antagonists exhibit an additive effect was not addressed [42]. Expression of mitochondrial Ang II within the mouse kidney provoked an increase in blood pressure, which was attenuated in mice with proximal tubule-specific deletion of the AT1 receptor or NHE3 [42]. Both AT1 receptor and NHE3 null transgenic mice without mitochondrial-targeted Ang II expression exhibited lower basal blood pressure than wildtype mice, suggesting these proximal tubule proteins play an important role in the maintenance of blood pressure within the kidney [42].

3. Heart Although cardiac tissue contains a relatively low density of Ang II receptors and very low Ang II content, there is extensive evidence for the intracellular expression of the AT1 receptor, as well as other G proteinecoupled receptors (GPRCs) [43,44]. DeMello [45,46] provided initial evidence that intracellular Ang II (as well as Ang I) can influence cardiac function in the isolated rat heart and adult cardiomyocytes isolated from the hamster. An ACE inhibitor blocked the intracellular actions of Ang I in the heart suggesting a functional ACE-dependent pathway within cardiomyocytes to generate Ang II. Tadevosyan et al. [47] demonstrated both AT1 and AT2 receptors on nuclei from adult male rats and that Ang II increased overall transcriptional activity in the nucleus. Interestingly, stimulation of nuclear transcription reflected the

4. Brain

contribution of both AT1 (increase in Ca2þ) and AT2 (increase in NO) receptors through different signaling pathways [47]. Ang II treatment of isolated nuclei from cardiomyocytes also stimulated an increase in Ca2þ by the AT1 receptor that was dependent on the release of IP3, which supports our previous results that PI3 kinase inhibition blocked the nuclear ROS response to Ang II [19,47]. Moreover, Ang II stimulated an increase in NFkB mRNA levels consistent with an inflammatory role of the peptide; however, the addition of both AT1 (valsartan) and AT2 (PD123177) antagonists was required to abolish the NFkB response to Ang II [47]. These latter findings raise the issue as to whether the nuclear AT2 receptor does not antagonize the actions of the AT1 receptor and may parallel or have additive effects to AT1 receptor signaling. In a more recent study on isolated canine cardiofibroblasts, Tadevosyan and colleagues [23] demonstrate that intracellular expression of a caged form of Ang II that is activated under UV light also stimulated Ca2þ, increased cell proliferation, and provoked collagen synthesis and release; however, the exact contribution of nuclear AT1 and AT2 receptors was not distinguished in this study. Moreover, intracellular levels of Ang II and the AT1 receptor were higher in cardiofibroblasts isolated from canines with congestive heart failure suggesting a potential role of the intracellular RAS in cardiac remodeling [23]. Indeed, previous studies documented elevated Ang II levels in cardiomyocytes from diabetic patients that were further increased in those patients with hypertension, as well as in isolated cardiomyocytes exposed to high glucose conditions [48e50]. Moreover, the targeted overexpression of either Ang II [51] or the precursor protein angiotensinogen [52] to the heart increased cardiac hypertrophy without an overall change in blood pressure. In isolated rat cardiomyocytes treated with extracellular Ang II, the Ang II receptor complex internalized; however, only the intracellular application of fluorescent Ang II trafficked to the nucleus [47]. To our knowledge, the localization of the Mas or MrgD receptors in cardiac nuclei or mitochondria has not been established, although the ACE2eAng-(1e7)eMas/MrgD receptor axis is considered to be cardioprotective [2,4].

4. Brain Sirett and colleagues [53] initially reported the localization of Ang II-binding sites in the nuclear and mitochondrial fractions from rat brain over 45 years ago; however, the potential role of a functional intracellular brain RAS has only been explored in the past several years [54e57]. In isolated nuclei from rat dopaminergic neurons, Villar-Cheda et al. [55] find that Ang II directly increased mRNA transcripts for PGC-1a, IGF-1, and the AT2 receptor; these responses were abolished by the AT1 receptor antagonist losartan. In lieu of the latter results, the authors propose that the nuclear response to Ang II reflects a compensatory action to buffer the deleterious actions of activation of the cell surface AT1 receptor through increased expression of PGC-1a, IGF-1, and the AT2 receptor. Ang II also elicited an increase in nuclear ROS (dihydroethidium fluorescence) that was abolished by losartan, DPI,

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and N-acetyl cysteine; however, the ROS signaling did not contribute to the increase in mRNA levels of PGC-1 or the AT2 receptor, which may reflect a novel signaling pathway to antagonize the deleterious actions of AT1 receptor stimulation [55]. The study also demonstrated that isolated nuclei expressed both the AT1 receptor and the NOX4 proteins consistent with previous studies on nuclear NOX4 in other tissues and cells [55]. Presumably, intracellular levels of Ang II would subsequently activate the nuclear AT2 receptor to stimulate additional pathways to antagonize the actions of AT1 receptor activation. Of particular interest, transient expression of AT1 and AT2 receptors in the dopaminergic N27 neuronal cell line revealed both cell surface and nuclear localization of both receptors suggesting the direct trafficking to the nucleus following receptor synthesis rather than ligand-mediated internalization of the surface receptor [55]. In regard to the intracellular Ang-(1e7) axis in brain, Valenzuela and colleagues [57] recently documented the expression of ACE2 and the Mas-related receptor MrgE in mitochondria isolated from rat dopaminergic neurons. Mitochondrial expression of ACE2 was markedly higher than the cell surface peptidase suggesting a unique pattern for the intracellular expression of the peptidase in brain [57]. Moreover, mitochondrial expression of the MrgE receptor was the predominant isoform of the Mas-related receptors including Mas, MrgD, and MrgF [57]. In this regard, the authors demonstrate that fluorescently labeled Ang-(1e7) and [Ala1]-Ang(1e7) bind to the MrgE receptor and that the DALA and [D-Pro7]eAng-(1e7) (DPRO) antagonists block the binding of both peptides, as well as the generation of NO. [Ala1]eAng-(1e7) treatment of isolated neuronal mitochondria also provoked an increase in NO, which was blocked by the DPRO antagonist [57]. Overall, these data suggest that the mitochondrial MrgE receptor lacks the fidelity of the Mas and MrgD receptors as MrgE does not distinguish the endogenous ligands Ang(1e7) and [Ala1]eAng-(1e7), nor differentiate between the two antagonists DALA and DPRO typically thought to discriminate the Mas and MrgD receptors [57]. Finally, the authors report reduced expression of both mitochondrial ACE2 [54] and MrgE [57] in aged rats (w20 months) as compared with 2e3-month old rats that may suggest an attenuated expression of the nonclassical RAS to buffer the actions of the Ang IIeAT1 receptor axis in aging within the brain. Although these findings contrast with our results in the renal mitochondria of sheep regarding the pathways for the generation of Ang-(1e7) (neprilysin/thimet oligopeptidase vs. ACE2), they importantly demonstrate the direct actions of Ang-(1e7) or its isoform [Ala1]eAng-(1e7) on mitochondrial function within the brain.

5. Intracellular RAS ligands The presence of intracellular receptors for Ang II and Ang-(1e7) necessitates the delivery and/or intracellular generation of the requisite ligands for these peptide receptors. Intracellular peptides may originate from the binding of the peptide to the cell surface receptor, internalization of the peptideereceptor complex, and

5. Intracellular RAS ligands

subsequent dissociation of the peptide into the intracellular space. Typically, dissociation of the peptide receptor complex occurs within lysosomes, and lysosomal enzymes would degrade the dissociated peptide that would obviate the targeting to intracellular receptors. However, Navar and colleagues [58,59] find that infusion of an Ang II isoform (bovine Val5eAng II) that readily binds AT1 receptors and is distinguished from endogenous Ang II (rat Ile5eAng II) accumulated to significant peptide levels in rat renal tissue, which were reduced in AT1 receptor null mice [60]. Van Kats et al. [61] reported comparable accumulation of intracellular levels of 125I-Ang II in nuclear, lysosomal, and microsomal fractions of the porcine kidney following infusion of the peptide, and the AT1 receptor antagonist eprosartan markedly reduced the intracellular levels of Ang II within kidney. The precursor protein angiotensinogen is the sole source of angiotensin peptides; however, angiotensinogen is synthesized and undergoes constitutive release by the cell into the extracellular space, which undergoes processing to Ang I and Ang II. As an alternative pathway to receptor-mediated uptake of Ang II, recent studies suggest that angiotensinogen is taken up and internalized by various cell types [62e70]. Pohl and colleagues [62] initially demonstrated that deletion of the megalin receptor in the mouse kidney reduced tissue levels of angiotensinogen within the renal proximal tubules. Matsusaka et al. [63] subsequently showed that knockdown of liver angiotensinogen markedly reduced the renal content of both angiotensinogen and Ang II. Conversely, knockdown of renal angiotensinogen had no effect on renal tissue angiotensinogen or Ang II but reduced urinary excretion of angiotensinogen that likely reflects synthesis and constitutive release of the protein by a subset of proximal tubules [63]. These investigators also demonstrate that induced glomerular injury enhances the renal levels of angiotensinogen and Ang II likely due to the increase in filtration of circulating angiotensinogen and uptake of the protein [64]. Indeed, Kukida et al. [65] recently confirmed that renal levels of angiotensinogen are dependent on liver angiotensinogen in nonhuman primates using chronic siRNA targeted to liver angiotensinogen. Although the precise pathways for the intracellular processing of angiotensinogen to Ang II (or Ang-(1e7)) remain to be established, the cellular uptake of angiotensinogen may be another source for intracellular expression of the requisite ligands for Ang II and Ang-(1e7) receptors. We find that mitochondria isolated from proximal tubules of the ovine kidney express both the 60-kD (high molecular weight or big renin) and the 37-kDa forms of active renin (Fig. 12.5) [71]. In this regard, Ishigami et al. [72] report the expression of an intracellular form of renin in the proximal tubule of the rat kidney, although the localization within the tubule cells was not determined. An intracellular form of renin was originally reported in the heart, brain, and adrenal gland and that intracellular renin traffics to the mitochondria in adrenal tissue and the cardiac H9 cell line [73e76]. This renin isoform reflects an alternative start site for transcription of renin that lacks the secretory sequence of the protease [76]. Isolated renal mitochondria from sheep express active renin, which readily cleaved exogenous angiotensinogen (disappearance of angiotensinogen using an Ang I-directed antibody), and trypsin treatment of renin conveyed no further increase in renin activity to hydrolyze the

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FIGURE 12.5 Expression of Renin and Angiotensinogen in Isolated Renal Mitochondria from Sheep. (A) Western blot reveals high molecular weight (HW, 60 kDa) and active (37 kDa) forms of renin in renal cortical mitochondria. (B) Mitochondrial renin cleaves exogenous angiote nsinogen (AI-Aogen) that is no longer recognized by a specific antibody to the Ang I (AI) region of Aogen. Pretreatment of mitochondria with trypsin did not increase renin activity (t1/2 of 30 vs. 33 mins) assessed by disappearance of AI-Aogen. (C) Western blot reveals total Aogen in isolated renal cortical mitochondria, but not intact AI-Aogen. (D) Peptide content of Ang-(1e7), Ang II, and Ang I assessed in C-18 extracted renal mitochondria by three separate RIAs. Data adapted from Wilson et al. Evidence for a mitochondrial angiotensin-(1e7) system in the kidney. Am J Physiol Renal Physiol 2016; 310: F637eF645.

precursor protein; treatment with the renin inhibitor aliskiren abolished the disappearance of intact angiotensinogen in the mitochondrial fraction (Fig. 12.5). The renal mitochondria also expressed endogenous angiotensinogen, although the majority of angiotensinogen was not intact as a specific antibody to Ang Ie angiotensinogen failed to detect the protein as compared with an antibody directed to an antigenic site distal to the Ang I sequence (Fig. 12.5). The absence of intact angiotensinogen may reflect the extended time to isolate the proximal tubules from the kidney that allowed for the extensive processing of angiotensinogen by renin, as well as the absence of a renin inhibitor during the isolation process.

5. Intracellular RAS ligands

Moreover, we find that Ang-(1e7) was the predominant peptide in the isolated renal mitochondria (w60 fmol/mg protein) with lower levels of Ang II and Ang I (Fig. 12.5). Costa-Breda et al. [54] also report higher levels of Ang-(1e7) than Ang II (w0.9 vs. w0.4 ng/mL or 1 pmol vs. 0.4 pmol/mL) in mitochondria from rat brain; however, these peptide concentrations were expressed as a volume (mL) rather than total protein, which precludes an accurate comparison of the peptide content between the two studies. In regard to the uptake of angiotensinogen, Wilson et al. [41] report that sheep proximal tubules readily internalized 125I-angiotensinogen, which was blocked by addition of excess unlabeled angiotensinogen, but not albumin (Fig. 12.6). The majority of internalized angiotensinogen accumulated in the nuclear and mitochondrial fractions of the sheep proximal tubules (Fig. 12.6). An autoradiograph of the isolated mitochondria from sheep proximal tubules and human HK-2 proximal tubule cells following uptake of 125I-angiotensinogen revealed a single protein band (w55 kD) consistent with the native size of the protein (Fig. 12.6). We note that Pan et al. [70] described a putative angiotensinogen receptor in primary human proximal tubule cells. This study demonstrated a high affinity-binding site for angiotensinogen (KD of 2 nM) and that unlabeled angiotensinogen, but not Ang II or losartan, displaced bound 125I-angiotensinogen [70]. The angiotensinogen-binding site complex was internalized by the proximal tubule cells in a temperature-dependent manner suggesting a cellular pathway for the internalization of the precursor protein; however, the identity of this site in the proximal tubules, other nonrenal tissues, and possibly intracellular sites remains to be identified. Finally, we recently demonstrated that human retinal epithelial cells internalize 125 I-angiotensinogen, and the precursor accumulated in the nuclear and mitochondrial fractions [68]. The uptake of angiotensinogen in the retinal cells was associated with a marked increase in oxidative stress [68]. In contrast, we failed to demonstrate significant uptake of 125I-labeled Ang I, Ang II, or Ang-(1e7) in the retinal cells or that extracellular Ang II stimulated an increase in ROS. Pretreatment of the retinal cells with the selective NOX1/4 inhibitor GKT137831 blocked the increase in ROS, but GKT137831 did not attenuate the cellular uptake of angiotensinogen [68]. The dynamin inhibitor dynasore blocked both the uptake of angiotensinogen and the increase in ROS, suggesting a clathrin-dependent process is responsible for the internalization of angiotensinogen [68]. Moreover, while the statin compound atorvastatin blocked the ROS response consistent with it’s antioxidant properties [77], atorvostatin failed to inhibit uptake of angiotensinogen [68]. Statins are reported to block megalin-dependent internalization of proteins, and the lack of an inhibitory effect of atorvastatin on angiotensinogen uptake suggests a megalinindependent pathway for angiotensinogen internalization in human retinal cells [77,78]. In this regard, Rong et al. [67] find that cardiofibroblasts internalize angiotensinogen by the lipoprotein receptor 1 (LRP-1) to stimulate inflammasomedependent fibrosis that may contribute to cardiac damage in this mouse model of sepsis. Indeed, this study suggests that the regulated expression of LRP-1 under pathological conditions contributes to the internalization of angiotensinogen and

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FIGURE 12.6 Uptake of Angiotensinogen in Sheep Proximal Tubules and in Isolated Mitochondria. (A) Subcellular distribution in renal cortical proximal tubules following uptake of 125I-angi otensinogen (Aogen) reveals the protein in nuclear (Nuc), mitochondrial (Mito), endopl asmic reticulum (ER), and cytosolic (cytosol) fractions. (B) Concentration-dependent increase in the uptake of 125I-Aogen in isolated renal cortical mitochondria. (C) Rate of 125 I-Aogen uptake in isolated mitochondria from sheep cortical proximal tubules and the human HK-2 proximal tubule cell line. Inset is an autoradiograph of the SDS gel revealing a single 125I band (55 kDa) corresponding to Aogen in mitochondria from sheep cortical proximal tubule and HK-2 cells following uptake of 125I-Aogen. (D) Uptake studies of 125IAogen as compared with 125I-labeled Ang I, Ang II, and Ang-(1e7) in isolated renal cortical mitochondria reveal markedly higher rate of Aogen uptake. Data adapted from Wilson B.A. et al., Angiotensinogen import in isolated proximal tubules: evidence for mitochondrial trafficking and uptake. Am J Physiol Renal Physiol 2017, 312: F879eF866.

potentially may regulate the expression of intracellular angiotensin peptides [67]. We acknowledge that we have not determined the fate of internalized angiotensinogen in either the ovine proximal tubules or the retinal cells; particularly whether the precursor is processed to Ang I by renin, potentially to Ang-(1e12) by nonrenin pathways [79,80] or other proteases that may directly generate Ang II or Ang(1e7); these pathways for the intracellular generation of angiotensin peptides awaits further study.

6. Summary

6. Summary The current chapter has examined various aspects of the intracellular RAS in the kidney, heart, and brain that encompass both the classical and alternative arms of this system. The biochemical and functional evidence clearly supports an intracellular ACE2eAng-(1e7)eMas or Mas-related receptor axis capable of antagonizing the ACEeAng IIeAT1 receptor arm of the RAS by ACE2-dependent metabolism of Ang II to Ang-(1e7) or via distinct pathways that limit the activation of Ang IIeAT1 receptor signaling. Indeed, evidence of an intracellular ACE2eAng-(1e7)eMas receptor axis that attenuates the Ang II-dependent stimulation of ROS on the nucleus and mitochondria emphasizes the potential importance of targeting this intracellular system as a therapeutic approach. The nucleus and mitochondria also contain various GPCRs including adrenergic (a, b1, b3) endothelin (EB), apelin, bradykinin (B2), glutamate, and endocannabinoid (CB1) receptors among others, and their potential interaction with Ang II or Ang-(1e7) receptors to influence cellular function has not been thoroughly evaluated to our knowledge [43,44,81]. Moreover, the extent that nuclear or mitochondrial angiotensin receptors undergo homo- or heterodimerization and the functional consequences of this interaction are unknown [82,83]. Finally, it is presently unclear how nuclear or mitochondrial GPRCs are regulated within the cell, particularly with respect to their cell surface counterparts regarding agonist-induced receptor desensitization, internalization, and further trafficking. Evidence that an altered Ang-(1e7) system within the kidney and brain again emphasizes an interaction between the Ang II and Ang-(1e7) pathways to promote cardiovascular dysfunction associated with fetal programming events and aging. Current therapies to attenuate an activated RAS include ACE inhibitors, AT1 receptor antagonists (ARBs), and renin inhibitors such as aliskiren. These approaches target the ACEeAng IIeAT1 receptor axis of the RAS; however, ACE inhibitors can increase circulating levels of Ang-(1e7) by blocking the metabolism of Ang(1e7) by ACE and shunting Ang I through an endopeptidase path independent of ACE2 [2]. ARBs can stimulate an increase in circulating Ang II and, to a lesser extent, Ang-(1e7) through the disinhibition of renin release. Thus, the effectiveness of these therapies may reflect, in part, the participation of the Ang-(1e7) or AT2 receptor-dependent pathways. Renin inhibitors are designed to block the initial enzymatic cascade in RAS activation, and subsequently, the downstream pathways stimulated by both Ang II and Ang-(1e7) would be attenuated. Agonists to both the Ang-(1e7) and AT2 receptors potentially combined with a renin inhibitor to preserve the alternative RAS pathways while blocking the Ang IIeAT1 receptor axis could be a potential therapeutic approach. Moreover, both the Mas receptor agonist AVE0992 and the AT2 receptor agonist C21 are nonpeptides that should traverse the cell membrane and activate intracellular receptors on the nucleus and mitochondria, although the extent that AVE0992 recognizes other Mas-related receptors is unknown. Aliskiren and ARBs are also nonpeptides that should target intracellular as well as extracellular sites, although ARBs exhibit different degrees of

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lipophilicity that influence the extent of their tissue permeability. Thus, the effective targeting of these intracellular pathways may convey additional benefit above that obtained by blockade of the extracellular or cell surface RAS.

Acknowledgments We gratefully acknowledge the exceptional efforts and expertise of former members of the laboratory including Alicia Allred, Karl Pendergrass, Bryan Wilson, Sarah Lindsey, Jonathan Cohen, Shea Gilliam, Allyson Marshall, Ebaa Al-Zayadneh, Nildris Cruz-Diaz, Brian Westwood, and Nancy Pirro, as well as honor the memory of our colleague and friend James Rose that have contributed to the studies in this chapter on the intracellular RAS. Portions of this work were supported by grants from the National Institute of Health grants (HL-46818, HL-56973, HL-51952, HD084227, HD-047584, HL091797, GM102773, HD-017644, HL155420) and the American Heart Association (AHA-151521 and AHA-355741). An unrestricted grant from the FarleyeHudson Foundation (Jacksonville, NC), Groskert Heart Fund and the Wake Forest Venture Fund is also acknowledged.

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CHAPTER

Interactions between the renineangiotensine aldosterone system and COVID-19: pharmacological interventions

13

Nada J. Habeichi1, 2, 3, Ghadir Amin1, 2, Gaelle Massoud1, 2, Reine Diab1, 2, Mathias Mericskay3, George W. Booz4, Fouad A. Zouein1, 2, 3, 4 1

Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon; 2The Cardiovascular, Renal, and Metabolic Diseases Research Center of Excellence, American University of Beirut Medical Center, Beirut, Lebanon; 3Department of Signaling and Cardiovascular Pathophysiology, Universite´ Paris-Saclay, Inserm, ChaˆtenayMalabry, France; 4Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center, Jackson, MS, United States

1. Introduction

1.1 The physiology of the renineangiotensinealdosterone system The renineangiotensinealdosterone system (RAAS) is one of the main regulators of blood pressure (BP) and fluid homeostasis and is composed of the three key proteins: renin, angiotensin II (ANG II), and aldosterone. The actions of the RAAS are highly coordinated through integrated actions in the cardiovascular system, the kidneys, and the central nervous system [1e3]. In addition to a pivotal role in regulating BP, the RAAS exerts an influence on different biological process including the immune response, cardiac function, cognition, and longevity [1,4e8]. The most biologically active peptide in the RAAS is the octapeptide ANG II that is produced through sequential enzymatic activity [9]. Activation of the sympathetic nervous system and decreased BP and blood volume stimulate renin expression, a tightly regulated enzyme produced by the renal juxtaglomerular (JG) cells [10]. Renin is produced as an inactive precursor that is cleaved by mircrosomes to generate prorenin [11]. Prorenin is then either secreted as the inactive form or converted into active renin by multiple proteases and stored in JG cells. Upon different stimuli, JG cells release renin into the circulation via exocytosis, which in turn cleaves the liver-secreted peptide angiotensinogen into the decapeptide angiotensin I (ANG I) that undergoes further cleavage in the kidney epithelial cells, endothelial Angiotensin. https://doi.org/10.1016/B978-0-323-99618-1.00006-4 Copyright © 2023 Elsevier Inc. All rights reserved.

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cells, and lung capillaries by angiotensin-converting enzyme (ACE), resulting in formation of ANG II, a vasoactive octapeptide [12,13]. Besides the role of ACE in the conversion of ANG I into ANG II, strong evidence has demonstrated that ACE can degrade vasodilating peptides such as bradykinin, kallikrein, and ANG (1e7) being therefore a main vasopressor enzyme [12,14]. One of the main actions of ANG II is the stimulation of aldosterone release, a mineralocorticoid steroid hormone, from the adrenal cortex [15]. Aldosterone activates mineralocorticoid receptors, complementing therefore the ANG II effects by increasing sodium and water retention, thus increasing blood volume to maintain balanced fluid and electrolyte levels [16]. Although aldosterone appears to exert beneficial effects in term of maintaining balanced blood volume and pressure, evidence has demonstrated that sustained increased levels of aldosterone are associated with exacerbated fibrosis and increased oxidative stress in multiple disease models [16,17]. ANG II has two major G proteinecoupled receptor subtypes: the angiotensin type 1 receptor (AT1R) and the angiotensin type 2 receptor (AT2R) [9]. It is well recognized that the ANG II/AT1R axis promotes vasoconstriction and enhanced proinflammatory response, proliferation, and apoptosis, whereas (in general) activation of the ANGII/AT2R axis counteracts these effects by enhancing vasodilatation and a subsequent decrease in BP, stimulating the antiinflammatory response, suppressing cell proliferation and growth, and promoting cell differentiation [18]. Recently, investigations have begun to shed light on the importance of another ACE isoform known as ACE2. ACE2 is a carboxypeptidase that has been shown to convert either ANG I (1e10) into ANG (1e9), which in turn is metabolized to ANG (1e7) by ACE, or degrade ANG II into ANG (1e7) that binds to the MAS receptor to induce its action [19,20]. The ACE2/ANG (1e7)/MAS axis is known to have a vasodilatory, antiinflammatory, and antifibrotic roles, opposing thus the actions of ANG II mediated by AT1R [21e23]. Therefore, an imbalance in ACE/ ACE2 activity will influence the extent of injury in response to stimuli that have an impact on the RAAS. Of note, ACE2 is expressed by cells of the lung, the heart, the kidneys, and the intestine, among other organs [24].

1.2 The renineangiotensinealdosterone system and SARS-CoV-2 ACE2 is the main cellular receptor for SARS-CoV-2 [25,26]. Upon cell entry, the virus downregulates the ACE2 receptor, the protective component of the RAAS, aggravating consequently COVID-19-associated inflammatory response, which can lead to a cytokine storm in multiple organs including high levels of tumor necrosis factor-a (TNF-a), monocyte chemoattractant protein-1, granulocyteemacrophage colony-stimulating factor, interleukin (IL)-1, IL-2, IL-6, IL-7, IL-18, and interferon gamma [27e31]. As previously stated, ACE2 is expressed in alveolar cells, cardiomyocytes, and proximal tubules of the kidneys, which may explain the observed severe complications in the lung, heart, and kidneys following SARS-CoV-2 infection [25,32,33]. Additionally, multiple studies indicate that SARS-CoV-2 leads to

1. Introduction

increased ANG II levels resulting perhaps in worsened outcomes and prognosis [34e36]. A small cohort study performed on COVID-19 patients indicated that plasma ANG II levels were positively linked to exacerbated disease severity and viral load [37]. Similarly, elevated ANG II levels in the context of COVID-19 have been shown to be associated with increased neutrophil infiltration, vascular permeability, and aggravated pulmonary edema, all of which can lead to acute respiratory distress syndrome (ARDS) [38]. Furthermore, a clinical retrospective study performed on 175 COVID-19 hospitalized patients showed that 62% developed hypokalemia, which was explained by an increased ACE/ACE2 ratio (decreased ACE2 expression and activity upon SARS-CoV-2 infection), stimulating thereafter aldosterone synthesis and subsequent hypokalemia, suggesting a potential beneficial effect of a mineralocorticoid blocker, which warrants further investigations [39]. Cardiac complications secondary to pulmonary pathology in the context of COVID-19 are well investigated. However, emerging studies suggest a potential direct interaction between COVID-19 and the cardiovascular system [40,41]. Based on transcriptomic analysis of adult human hearts, high expression of ACE2 in pericytes was noted drawing attention to whether pericytes play a central role in observed cardiac complications [40]. Using cellecell interaction analysis, prominent communication between pericytes and endothelial cells was revealed [41]. The damage to pericytes could thus propagate to the endothelium resulting in increased microvascular permeability facilitating the entry of proinflammatory cells. This scenario was postulated to be a potential mechanism in COVID-19-induced thrombotic events. Another mechanism that could play a critical role in SARSCoV-2-mediated cardiac injury is increased ACE2 levels in patients with preexisting CVDs. In that regard, it has been reported that patients with heart failure in the presence or absence of transplantation showed a marked upregulation in ACE2 expression levels in myocytes and fibroblasts, heightening therefore a greater likelihood of developing myocarditis and thus increased mortality rate post-COVID-19 in those patients [41,42]. In addition to the observed upregulation in cardiac ACE2 in patients with preexisting CVDs, other basic investigations reported that even the healthy heart expresses multiple accessory proteins that facilitate SARS-CoV-2 entry and infectivity including TMPRSS2, CD147, neutrophil-1 receptor, and integrin a1b5, thus enhancing cardiac damage and cellular injury by SARS-CoV-2 [43e46]. Collectively, it is clear that ACE2 expression and activity are a key player in the context of COVID-19. The exact role, however, is complex and yet to be fully understood. ACE2 could exert deleterious effects in the infection phase since it is the major receptor for SARS-CoV-2, whereas it could play a beneficial role in the inflammatory phase by dampening the cytokine storm through the activation of ACE2/ANG [1e7]/MAS axis. Based on the strong interaction between RAAS and SARS-CoV-2, we summarize in this chapter what is known or surmised about the impact of RAAS inhibitors including direct renin inhibitor, angiotensinconverting enzyme inhibitors (ACEIs), angiotensin type 1 receptor blockers (ARBs), aldosterone inhibitors, beta-blockers, heparin, and glucocorticoid on COVID-19 progression and development (Fig. 13.1).

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FIGURE 13.1 SARS-CoV2 is shown to have a direct impact on the RAAS system mainly through incre asing ANG II and empowering the detrimental ACE/ANG II/AT1R arm, and reducing ACE2 and weakening the protective ACE2/ANG (1e7)/MAS arm, hence lowering prognosis (A). Numerous drugs and drug classes including renin inhibitors, b-blockers, ACE inhibitors, spironolactone, heparin, ARBs, and glucocorticoids are shown to inhibit different parts of the RAAS that could improve prognosis post-COVID-19 infection mainly through reducing the detrimental ACE/ANG II/AT1R arm effects (B).

2. Renineangiotensinealdosterone system therapeutic venues in the context of SARS-CoV-2 infection 2.1 Direct renin inhibitor

Direct renin inhibitors have recently come into play as a potential promising therapy for hypertension. Aliskiren (aka SPP100), an oral, nonpeptide, low-molecularweight renin inhibitor, exerts a unique antihypertensive properties by depressing RAAS activity at the rate-limiting step, resulting in inhibiting formation of both ANG I and ANG II as well as decreasing renin activity [47]. The number of studies showing the potential protective effect of aliskiren in the context of COVID-19 is scant. In a preliminary clinical study conducted on four elderly hypertensive patients with severe COVID-19, administration of aliskiren in combination with another drug (one patient with aliskiren plus a diuretic and three with aliskiren plus a calcium channel blocker) showed a decrease in BP, proof of the potential beneficial use of

2. Renineangiotensinealdosterone system therapeutic venues

aliskiren as hypertensive therapy in severe COVID-19 patients [48]. Additionally, due to the lack of a conclusive conclusion about the benefiterisk ratio of using ACEIs and ARBs in the context SARS-CoV-2 infection, aliskiren appears as an alternative therapy that provides the necessary inhibition of RAAS without upregulating ACE2 levels [49,50]. Further preclinical investigations and clinical studies are needed to discern the exact role and molecular consequences of direct renin inhibitors post-COVID-19 infection.

2.2 ACEIs/ARBs Multiple emerging studies have suggested that ACEIs and ARBs could exert beneficial effects in the setting of COVID-19 infection. ACEIs are widely known to inhibit the conversion of ANG I to ANG II, whereas ARBs are a newer class of drug that selectively block ANG II type I receptors [51,52]. These two types of RAAS inhibitors have been observed to reduce mortality rate and to protect against cardiac diseases including myocardial infarction, stroke, and cardiac arrest via numerous mechanisms including the suppression of oxidative stress and the prevention of protein glycosylation [21,53]. ACEIs and ARBs have also been described as promising therapies in the setting of hypertension and type 2 diabetes mellitus [54,55]. With the pandemic, a growing body of evidence has demonstrated that ACEIs/ ARBs could exert protective effects post-SARS-CoV-2 infection through two main mechanisms: first by upregulation of ACE2, the protective arm of RAAS, regulating therefore the severity of pulmonary edema and progression and development of CVDs [25]; and second by depressing the observed marked increase in ANG II post-COVID-19, which is known to exert detrimental impact either directly on the cardiovascular and pulmonary systems or indirectly by exacerbating the overactivation of the immune system, known as the cytokine storm [56e58]. In that regard, studies have documented that COVID-19 hypertensive patients treated with ACEIs/ARBs have lower mortality rate compared with control groups on other antihypertensive medications [59e62]. In addition to the observed protective effects of ACEIs/ARBs in decreased death rate, Wang et al. and Negreira-Caamano documented decreased ventilator support in hospitalized COVID-19 patients with hypertension treated with ACEIs/ARBs [63,64]. Furthermore, Yang et al. observed a decrease in proinflammatory markers CRP and procalcitonin levels in COVID-19 patients with preexisting hypertension and on ACEIs/ARBs treatment [65]. A downregulation of IL-6 plasma levels along with an upregulation of CD3 and CD8 (T cell markers) was also observed in hypertensive patients with COVID-19 treated with ACEIs/ARBs, suggesting that this treatment could dampen the observed exacerbated proinflammatory response and preserve peripheral T cells poolemediated antiviral effect [66]. The observation that ACE2 is beneficial in tamping down the adverse effects of the ACE/ANG II/AT1R axis, yet serves as a route for SARS-CoV-2 cellular entry, suggests that this enzyme has a double-edge role in COVID-19. Recent evidence

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highlighting the potential involvement of soluble ACE2 (sACE2) in the observed adverse outcomes illustrates the complex role of ACE2 in the setting of SARSCoV-2 infection. In a prospective cohort of hospitalized COVID-19 patients, the authors documented an elevation in sACE2 at admission, but this increase was not associated with disease severity or mortality. Instead, they reported a marked decrease in sACE2 levels in surviving patients along with an increase in patients who died from COVID-19 [67]. ACE2 is cleaved by a disintegrin and metalloprotease 17 (ADAM17), which mediates shedding of different surface proteins including ACE2, releasing it thereafter into circulation as sACE2 [9,68]. Increased ANG II levels along with enhanced inflammatory response, the hallmark of COVID19, are known to activate ADAM17, leading subsequently to a detrimental positive feedback loop, mediated by the ANG II/AT1R axis that further activates ADAM-17, resulting therefore in enhanced shedding of tissue ACE2, consequently a downregulation in tissue ACE2 levels and an upregulation in sACE2 [25,69]. Of note, increased ACE2 shedding by ADAM17 has been demonstrated to be associated with increased death rate and incidence of acute myocardial infarction, atrial fibrillation, and coronary artery disease [67,70,71], suggesting a critical role of ACE2 tissue loss in worsening both cardiovascular diseases and SARS-CoV-2 severity. In addition to increased ANG II levels, a decrease in ANG (1e7) due to a downregulation in ACE2 following SARS-CoV-2 infection may exert detrimental effects. Elevated ANG (1e7) levels have been observed to activate the PI3K-AKT pathway, leading to enhanced nitric oxide synthase 3 activation, consequently increased NO production and lessened cardiac damage [72]. Furthermore, Gomes et al. indicated that increased ANG (1e7) inhibits the translocation of nuclear factor of activated T cells (NFAT) to the nucleus, downregulating therefore hypertrophic genes and maladaptive cardiac remodeling [73]. In addition to the early controversy surrounding inhibiting RAAS in the context of COVID-19 due to preclinical evidence of increased ACE2 expression in animals treated with ACEI/ARBs [74], a tissue-specific pattern of ACE2 expression in response to this virus has also been observed. For instance, in alveolar epithelial and pulmonary endothelial cells, ACE2 expression was increased post-COVID-19 infection, which could serve as a viral gate into human cells or compensate against elevated ANG II-mediated tissue damage. Conversely, in vascular endothelium, a downregulation of ACE2 expression was seen and accompanied by exacerbated myocardial fibrosis and enhanced immune cell infiltration, worsening adverse outcomes thusly in COVID-19 patients [75,76]. Others investigations, however, reported no significant association between the inhibition of the RAAS by ACEIs/ARBs and COVID-19 severity and mortality [74,77e79]. Collectively, the benefits of inhibiting the RAAS by ACEIs/ARBs post-COVID-19 remain questionable and require further clinical investigation.

2.3 Aldosterone inhibitors (spironolactone) Spironolactone, commonly known as a potassium-sparing diuretic, is a mineralocorticoid (aldosterone) receptor (MR) antagonist used primarily to treat heart failure, hypertension, hyperaldosteronism, and edematous states [80]. Aldosterone is the

2. Renineangiotensinealdosterone system therapeutic venues

physiological MR activator that acts as a principal regulator of fluid and electrolyte homeostasis [81]. Spironolactone competes with aldosterone for receptor sites and ultimately reduces sodium reabsorption and decreases potassium excretion. Aside from the epithelial target, it is now well established that aldosterone has a detrimental impact on the pulmonary, renal, and cardiovascular systems by promoting fibrosis, inflammation, and immune cells activation. It polarizes macrophages toward the M1 proinflammatory phenotype, favors CD4þ lymphocyte differentiation toward proinflammatory Th17 cells, and induces cytotoxic IFNgþ-CD8þ lymphocytes [82]. Antagonizing MR was shown to block these actions, thus attenuating the inflammatory cascade and end-organ damage. Additionally, spironolactone also possesses an antiandrogenic effect and is sometimes used “off-label” to treat hirsutism, female pattern hair loss, and adult acne vulgaris [83]. Current data highlight a prominent interplay between the actions of spironolactone and the process of COVID-19 infectivity and progression [84]. The infectivity of COVID-19 depends on ACE2 and on the transmembrane serine protease 2 (TMPRSS2) expression for viral priming on the S protein. Spironolactone has been shown to boost sACE2 levels in plasma [85]. In addition, spironolactone may concomitantly downregulate the expression of TMPRSS2 through its antiandrogenic effect. As such, it may preclude the virus from cell entry by reducing membrane-attached ACE2 from coupling to the virus and by reducing the critical activity of TMPRSS2. In particular, this would mitigate lung pathogenicity, where 80% of the total ACE2 expression in the body resides, with associated complications such as ARDS and pulmonary edema [86]. Besides the favorable RAAS and ACE2 patterns, spironolactone has antiinflammatory and antifibrotic properties that can offer protection to organs centrally affected by COVID-19 such as the lungs, heart, and kidneys. These mechanisms suggest an advantageous effect of spironolactone at all stages of COVID-19. Studies have confirmed a high prevalence of hypokalemia among COVID-19 patients suggesting a disrupted RAAS and potential hyperaldosteronism [87]. An open-label nonrandomized comparative clinical trial conducted by V. Yu et al. showed that a combination of bromhexine with spironolactone in patients with mild and moderate COVID-19 accelerates the normalization of the clinical condition and lowers the temperature one and a half times faster, by reducing the combined endpoint of viral load or long duration of hospitalization [88]. The presentation of spironolactone as a candidate for COVID-19 remains theoretical, but it created the base for several active trials (for example, NCT04643691, NCT04424134, NCT04826822).

2.4 Beta-blockers Beta-adrenergic receptor antagonists (b-blockers) are commonly used to treat cardiovascular conditions such as hypertension, arrhythmias, and myocardial infarction. By competitively binding to the b-adrenergic receptors, b-blockers inhibit the sympathetic effect of catecholamines, epinephrine, and norepinephrine, reducing the adrenergic tone of cardiac muscle and pacemaker cells resulting consequently in

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reduced heart rate (chronotropy), cardiac contractility (inotropy), conduction velocity (dromotropy), and the rate of myocardial relaxation (lusitropy). In the kidneys, b-blockers can interfere with the RAAS by binding to the b1-adrenoreceptors on JG cells, thereby directly suppressing the release of renin [89]. Catecholamines are important regulators of the cardiovascular, respiratory, and immune systems. Therefore, it is likely that COVID-19 patients exhibit sympathetic storm that produces major complications. A stimulated adrenergic system can promote virus invasion by stimulating renin secretion, RAAS activity, and ACE2 expression [90]. By acting on upstream renin, b-blockers offer an advantage over ACEIs and ARBs by suppressing the production of ANG II and its detrimental effects. Following infectivity, excessive activation of the host immune response results in a hyperinflammatory state [91]. Catecholamines can augment the cytokine storm through integrated feed-forward loops and mainly through the b2 adrenergic pathway activation. For instance, many of the cytokines generated in SARS-CoV2-infected patients including IL-6, TNF-a, and IL-1b, are engaged in Th17 activation, which constitutes a key target to the catecholamine response [92]. Inhibition of the b2-adrenergic pathway was shown to reduce inflammatory cytokines and Th17 activation in cancer and autoimmune disease [93,94]. Furthermore, the accumulation of inflammatory mediators predisposes to ARDS, the need for mechanical ventilation, and septic shock [95]. b-Adrenergic blockers were demonstrated to reduce mortality in ICU patients with acute respiratory failure [96]. More recently, a pilot study conducted by Clemente-Moragon et al. on 20 COVID-19 patients with ARDS on invasive mechanical ventilation showed the effectiveness of intravenous administration of metoprolol for 3 days (3  5 mg boluses daily) in reducing lung inflammation, as evidenced by the decreased neutrophil and monocyte/macrophages content in bronchoalveolar lavage [97]. Additionally, metoprolol administration resulted in better oxygenation with fewer days spent on invasive mechanical ventilation [97]. Chouchana et al. also reported a lower risk of in-hospital mortality by comparing the effect of beta-blockers to other antihypertensive drugs, with at least 30 days follow up [98]. Furthermore, a retrospective analysis for elderly infected patients revealed an association of b-blockers with decreased mortality and dyspnea [98]. A plausible effect for beta-blockers in counteracting COVID-19-associated sympathetic activation, cytokine storm, and severe disease is therefore suggested. Conversely, other studies indicated potential beneficial effects of sympathetic nervous system activation in the setting of COVID-19 based on the type of receptor. For instance, upon the interaction of noradrenalin/adrenalin with a1-AR and b2-AR receptors, a decrease in bronchial gland secretion along with improved ventilation was observed. Additionally, the interaction of catecholamine with a1-AR/b2-ARinduced vasoconstriction may reverse cardiogenic shock in COVID-19 patients [99]. These controversial data call for further prospective investigations to confirm the potential importance for using b-blockers in treating COVID-19.

2.5 Heparin Heparin, mostly known for its anticoagulant/antithrombotic properties, acts mainly by potentiating the action of the endogenous anticoagulant antithrombin III [100].

2. Renineangiotensinealdosterone system therapeutic venues

The latter inhibits the action of coagulation factors Xa and IIa, thus stopping the coagulation cascade and fibrin clot formation [100]. Heparin not only acts on antithrombin III, but it also potentiates the effect of many endogenous anticoagulants such as heparin cofactor II (HCII), protein C inhibitor (PCI), and tissue factor plasminogen inhibitor (TFPI) but to a lesser extent [100]. Although heparin is widely used for its antithrombotic properties, an antihypertensive effect has been attributed to this drug due to its potential action on the RAAS. In a study done on hypertensive rats, Susic et al. showed that subcutaneous administration of heparin lowered their blood pressure by decreasing aldosterone levels; however, renin and angiotensin levels remained elevated [101]. It is postulated that the decrease in aldosterone levels is due to the reduction in number and affinity of ANG II receptors, as well as to the decrease in the width of the zona glomerulosa [102]. Heparin has been used in the treatment of COVID-19 prophylactically or therapeutically mainly to reduce coagulopathy and thrombus formation. Several randomized controlled trials (RCTs) studied the effect of heparin in COVID-19 patients. It has been reported that the risk of developing thromboembolism in critically ill COVID-19 patients was 28.7% following the administration of a therapeutic dose of low-molecular-weight heparin (LMWH). Following prophylactic dose, the percentage increased to 41.9% [103]. Other RCTs showed that therapeutic dose increased survival until hospital discharge in patients with moderate COVID-19, but not in severe cases [104,105]. Not only has it been used for its antithrombotic properties, but also for its antiinflammatory, anticomplement, and antiviral effects. Due to its polyanionic nature, heparin can bind complement proteins and acute phase reactants, thus decreasing immune cell activation and inflammation [106,107]. It can also interact with cytokines and chemokines, resulting in a conformational change and preventing them from binding to their receptors [108e110]. For instance, a reduction in proinflammatory cytokines IL-6 and IL-8 levels has been noted following heparin administration [111,112]. A retrospective cohort studied the antiinflammatory effect of LMWH and the severity of disease progression in COVID-19 patients. They have found a decrease in hypercoagulable state and IL-6 [113], thus shedding light on the antiinflammatory properties of the drug. Heparin also prevents the activation of the proinflammatory signaling pathway mediated by nuclear factor-kappa B (NF-kB), STAT3 and MAPK [114] by interacting with these cytosolic transcription factors and preventing their translocation to the nucleus [115,116]. The antiviral properties of heparin are due to its interaction with SARS-CoV-2 spike S1 receptor-binding domain (RBD), which prevents cellular invasion. It is known that S1 RBD not only relies on its binding to the ACE2 receptor for cellular entry but also requires a receptor made of heparan sulfate to facilitate adhesion to cell surface [117]. Heparin, being structurally similar to heparan sulfate, interacts with the spike (S1) receptor binding domain of SARSCoV-2 and also prevents viral entry [118]. Therefore, given its antiinflammatory, antiviral, anticoagulant effects, heparin could be considered as a beneficial therapeutic option against COVID-19.

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2.6 Glucocorticoids Glucocorticoids inhibit many inflammatory molecules such as chemokines, cytokines, adhesion molecules, and arachidonic acid metabolites [119]. They act by binding to the glucocorticoid receptor in the promotor region of genes or by interacting with transcription factors such as activating protein-1 (AP-1) or NF-kB [120]. Dexamethasone, a commonly used corticosteroid, was shown to inhibit RAAS and improve renal response to atrial natriuretic peptide (ANP) by increasing expression of natriuretic peptide receptor-A (NPR-A) [121,122]. Dexamethasone has been indicated for the treatment of COVID-19. Several systematic reviews looked at the safety and efficacy of systematic corticosteroids in critically ill COVID-19 patients. They have found that corticosteroids reduced all-cause mortality and disease progression in hospitalized individuals [123,124]. However, the results of Ma et al. were largely influenced by the RECOVERY trial. The repeated analysis excluding RECOVERY did not show survival benefit [123,125]. To note, the RECOVERY trial showed a decrease in incidence of death among patients receiving systemic corticosteroids on invasive mechanical ventilation or supplemental oxygen, but not in those without additional oxygen support [125]. However, more RCTs are needed to draw a definitive conclusion about the efficacy of corticosteroids. The trials included in the systematic reviews exhibit marked heterogeneity and moderate risk of bias [123]. The benefits of corticosteroids lie in their antiinflammatory properties as they dampen the cytokine storm generated by COVID-19 [126]. Studies have attributed an effect of corticosteroids on several signaling molecules. For instance, corticosteroids can attenuate the NF-kB signaling pathway, which plays a role in inflammatory lung disease. The pathway is also constitutively activated in COVID-19 due to the viral inhibitory effect on the inhibitor IkBa [127]. Additionally, NF-kB is required for IL-6 and TNF-a cytokine induction [127]. Interestingly, along with NF-kB, IL-6 can also be induced by ANG II via AT1R [128]. Therefore, glucocorticoids decrease IL-6 production not only by inhibiting NF-kB but also by interfering with RAAS activation. To attribute only an antiinflammatory effect for corticosteroids would be too simplistic, as they have been shown to induce expression of several other proteins that protect against COVID-19. For instance, it has been indicated that the drug could strengthen the barrier function of the lung endothelium by increasing plasma sphingosine 1-phosphate levels [129]. Hence, dexamethasone acts synergistically with the proinflammatory milieu to provide optimal efficacy and protection against SARS-CoV-2 [130].

3. Perspectives Overall, the use of ACEIs and ARBs seems to be associated with reduced risks of COVID-19 disease [131]. The utility of targeting ACE2 in preventing SARSCoV-2 infection is uncertain, however. Although ACE2 represents a major route for virus entry, the ACE2/ANG (1e7)/MAS arm of the RAAS is an important counterweight to the actions of the ACE/ANG II/AT1R arm. What has become clear in

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recent years is the fact that the two act together to maintain homeostasis. Without the ACE2/ANG (1e7)/MAS arm, the maladaptive actions of the ACE/ANG II/AT1R arm are enhanced. While targeting the ACE/ANG II/AT1R arm, however, the increase in ACE2 levels may promote the virulence of SARS-CoV-2, which hinders a significant improvement in prognosis. Left to be fully understood is how regulation of the two arms are coordinated. While the consequences of COVID-19 have been tragic on many levels, this pandemic has highlighted the need to understand better the regulation of ACE2 and the therapeutic potential of targeting the ACE2/ANG (1e7)/MAS arm.

Acknowledgments This work was supported by grants from the American University of Beirut Faculty of Medicine (grant number MPPd320145/320095; URBd103949) and by Centre National de la Recherche Scientifique (CNRS) (grant number 103507/103487/103941/103944) to FAZ; and Agence Nationale de la Recherche (ANR) (grantdANICOV-HF) to FAZ and MM. GWB acknowledges the support of the Department of Pharmacology and Toxicology at the University of Mississippi Medical Center.

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Angiotensin II and its action within the brain during hypertension

14

Srinivas Sriramula1, Vinicia Campana Biancardi2, 3 1

Department of Pharmacology and Toxicology, Brody School of Medicine at East Carolina University, Greenville, NC, United States; 2Anatomy, Physiology and Pharmacology Department, College of Veterinary Medicine, Auburn University, Auburn, AL, United States; 3Center for Neuroscience Initiative, Auburn University, Auburn, AL, United States

List of abbreviations ACE ACE2 AngII AP AT1r BBB BK CNS CPM CPN CVOs DABK DAKD IL-10 IL-1bd IL-6 IML iNOS KD KKS NEP NFkB NTS OVLT PICs PVN RAS ROS RVLM SFO

angiotensin-converting enzyme angiotensin-converting enzyme 2 angiotensin II area postrema Angiotensin II type 1 receptor bloodebrain barrier bradykinin central nervous system carboxypeptidase M carboxypeptidase N circumventricular organs des-Arg9-BK des-Arg10-KD interleukin-10 interleukin-1 beta interleukin-6 intermediolateral cell column inducible nitric oxide synthase kallidin kallikreinekinin system neutral endopeptidase nuclear factor kappa B nucleus tractus solitarius organum vasculosum of the lamina terminalis proinflammatory cytokines paraventricular nucleus of the hypothalamus renineangiotensin system reactive oxygen species rostral ventrolateral medulla subfornical organ

Angiotensin. https://doi.org/10.1016/B978-0-323-99618-1.00017-9 Copyright © 2023 Elsevier Inc. All rights reserved.

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SHR TLR TLR4 TNF-a

spontaneously hypertensive rat Toll-like receptor Toll-like receptord4 tumor necrosis factor-alpha

1. Introduction The renineangiotensin system (RAS) is traditionally recognized as a critical regulator of blood pressure as well as water and electrolyte homeostasis. In addition to its classical peripheral actions, angiotensin II (AngII), the main active peptide of RAS, can also act as a neurotransmitter within the central nervous system (CNS). Under normal conditions, blood-borne AngII is a large peptide that may access the brain through regions of the brain that lie outside the bloodebrain barrier (BBB). Indeed, AngII receptors, particularly AngII type 1 receptor (AT1R), have been found in various circumventricular organs (CVOs), such as the subfornical organ, vascular organ of the lamina terminalis, and area postrema [1]. Circulating AngII signaling within the CVOs influences efferent projections from CVOs to a network of CNS nuclei controlling the cardiovascular function within the hypothalamus and brainstem, including the paraventricular nucleus of the hypothalamus (PVN), the rostral ventrolateral medulla (RVLM), and the nucleus tractus solitarius (NTS) [2,3]. The PVN is a major regulator of sympathetic outflow via direct projections to the spinal cord’s intermediolateral cell column (IML) or indirectly via RVLM presympathetic neuron projections [4]. Furthermore, the PVN sends and receives projections from the NTS, which influences baroreflex as well as sympathetic activity [5,6] (Fig. 14.1). Accordingly, both the hypothalamic and brainstem cardiovascular nuclei

FIGURE 14.1 AngII and Neural Networks Influencing Sympathetic Outflow. Summary outline of nuclei and neural networks in which AngII has been shown to act as a neurotransmitter to promote cardiovascular homeostasis. In hypertension, dysregulation of AngII signaling eventually leads to increased sympathetic activity. SFO, subfornical organ; OVLT. organum vasculosum of the lamina terminalis; PVN, paraventricular nucleus of the hypothalamus; RVLM, rostroventrolateral medulla; NTS, nucleus of tract solitarius; AP, area postrema; IML, intermediolateral cell column. Created with BioRender.com.

2. Hypertension and angiotensin II

cited have shown AT1R expression [1]. Notably, exacerbated AngII signaling within those nuclei is associated with baroreflex impairment and increased sympathetic activity, both hallmarks of hypertension [7]. In addition to circulating AngII accessing the brain through CVOs, all components of RAS have been found within the brain, including angiotensinogen, renin, prorenin, angiotensin-converting enzyme, AngII, and AngII type 1 and 2 receptors [1,8,9]. Hence, circulating and tissue-specific AngII influence the CNS to maintain cardiovascular homeostasis. The effects of AngII acting as a neurotransmitter in the CNS associated with hypertension is complex and involves several critical mechanisms. This chapter provides a brief update on recent work concerning AngII actions within the brain during hypertension, emphasizing AngII effects on the bloodebrain barrier, innate immune system, and, more recently, the bradykinin system. In several instances, review articles rather than original research are cited to facilitate the reader who is interested in understanding further AngII actions in the brain. Original research references are mentioned within the review articles.

2. Hypertension and angiotensin II Hypertension is a complex and multifactorial disease. Due to the linear relationship between high blood pressure and risk for the development of other cardiovascular debilitating events, a trend to reflect the need for intervention at earlier stages of high blood pressure (i.e., systolic blood pressure of 130 mmHg) has been recently updated [10]. AngII dysregulation has long been implicated as a culprit in the development and maintenance of severe essential hypertension, renal hypertension, and malignant hypertension in adult patients [11] and children with essential hypertension [12]. Historically, drugs targeting the RAS have been approved for the management of hypertension since the early 1980s with the discovery of the angiotensinconverting enzyme (ACE) inhibitor captopril [13] and later with the AT1R blockers sartans [14]. Still, despite a plethora of pharmacological interventions available to treat hypertension, many hypertensive patients are resistant to pharmacological treatment even when three or more different classes of antihypertensive therapy (most regimens including RAS inhibitors) are administered [15]. A common characteristic of resistant and difficult to treat patients is an increase in sympathetic activity [16]. Independent of its effects on treatment, a progressive activation of sympathetic activity in hypertension is associated with end-organ damage and increased risk of cardiovascular, renal, and metabolic diseases [17]. As outlined in the introduction, there is anatomical evidence supporting the ability of both circulating and central AngII within the CNS to influence sympathetic outflow. Likewise, several functional studies have shown a positive interaction between AngII and increases in sympathetic activity. For instance, AngII directly injected within the PVN induces a pressor response mediated by the sympathetic

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system, measured through the effects of a ganglionic blockade [18]. Blockade of angiotensin receptors within the RVLM and NTS removes excitatory vasomotor tone and inhibits the modulation of the baroreflex response to the heart sympathetic activity, respectively [19,20]. In this chapter, we highlighted AngII system interactions in which AngII is also shown to modulate sympathetic activity during hypertension.

3. Angiotensin II increases bloodebrain barrier disruption in hypertension As discussed earlier in this chapter, AngII is a sizable hydrophilic peptide that usually does not cross the BBB. Circulating AngII is thought to enter the brain through neural areas devoid of BBB, and the CVOs, and influence the control of cardiovascular function by activating key central pathways involved in blood pressure regulation and blood fluid homeostasis [2,3]. During hypertension, various investigators have shown that AngII promotes an increase in BBB permeability [21e27], which enables an additional route for peripheral AngII to enter the brain. Notably, the disruption of the BBB has been observed within cardiovascular regulatory nuclei such as the PVN, RVLM, and NTS, and labeled AngII injected peripherally can enter those nuclei [21] (Fig. 14.2). Hence, it is essential to consider that actions of circulating AngII and

FIGURE 14.2 Angiotensin II is Associated with BloodeBrain Barrier Disruption. In normotensive conditions, plasma AngII enters the brain through circumventricular organs devoid of BBB, such as the subfornical organ, organum vasculosum of the lamina terminalis, and area postrema (SFO, OVLT, and AP) to influence sympathetic outflow. In hypertension, elevated plasma AngII levels and/or locally produced AngII disrupt BBB and access cardiovascular nuclei directly, exacerbating sympathetic outflow. PVN, paraventricular nucleus of the hypothalamus; RVLM, rostroventrolateral medulla; NTS, nucleus tract solitarius; IML, intermediolateral cell column; BBB, bloodebrain barrier. Created with BioRender.com.

4. Angiotensin II, innate immune system, neuroinflammation

locally produced AngII within the brain of hypertensive states are difficult to distinguish. Still, independent of the origin, AngII is known to promote hypertension by releasing vasopressin, modulation of baroreflex, and body fluid dyshomeostasis, promoting neuroinflammation and enhancing sympathetic outflow [21e28].

4. Angiotensin II, innate immune system, neuroinflammation, and hypertension Both innate and adaptive chronic immune system activation plays a critical role in developing hypertension (reviewed in Ref. [29]). Given that both immune system activation and AngII contribute to hypertension, several investigators have studied whether there is a causal relationship between AngII, acting mainly through AT1R, and the immune system in the modulation of blood pressure. In addition, there is substantial evidence that chronic low-level neuroinflammation in dysfunctional AngII signaling hypertensive models is associated with increased sympathetic activity [30e32], highlighting the critical role of AngII as a proinflammatory molecule. The focus of this section is to highlight the work involving AngII, the innate immune system, and neuroinflammation within brainecardiovascular nuclei during hypertension. However, as mentioned before, it should be noted that while the studies discussed highlighted effects of AngII within the brain, whether AngII signaling involved in neuroinflammation is prevenient from the periphery or produced in situ is still not understood.

4.1 AngII-induced microglia activation Microglia are the resident and primary innate immune effector cells of the brain. Microglia are dynamically engaged in surveillance of the environment during physiological conditions, constantly sensing the brain parenchyma to maintain homeostasis. Once microglia senses changes in the brain microenvironment, it enters into an “activated” mode, characterized by morphological and phenotypical changes, and regulates the innate immune system by initiating a proper response, such as inflammation [33]. During hypertension, several studies have demonstrated that elevation in blood pressure in hypertensive animal models associated with AngII dysfunction is accompanied by microglial activation and/or elevated proinflammatory cytokines (PICs). In AngII-induced hypertensive rats, inhibition of microglia by infusing minocycline intracerebroventricularly causes attenuation of blood pressure associated with a decrease in numbers of activated microglia cells, a reduction in PICs mRNA expression (IL-6, IL-1b, and TNF-a), and increase in antiinflammatory cytokine IL-10 mRNA expression within the PVN [34]. Additionally, targeted depletion of microglia within the PVN of AngII-induced hypertensive animals attenuates blood pressure alongside a decrease in neuroinflammation and glutamate receptor expression within the PVN, plasma vasopressin level, and kidney norepinephrine concentration [35].

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Increased microglial activation in the PVN and RVLM, as observed through changes in morphological parameters and/or gene expression studies (P2Y12R and CX3CR1), coupled with an increase in PICs (TNF-a, iNOS, IL-1b, and IL-6), were also found in spontaneously hypertensive rats (SHRs), suggesting a constant level of low-grade inflammation in these nuclei during hypertension [36e38]. Neuroinflammation and AngII signaling cross-talk can also be evidenced as SHRs treated with the AT1R blocker losartan demonstrated a decrease in blood pressure alongside changes in the microglia morphology indicative of a noninflammatory profile, as well as a reduction of PICs within the PVN and RVLM [38]. Collectively, the aforementioned studies indicate a role for microglial activation and an increase in the proinflammatory profile within the hypothalamus and brainstem of different models of hypertension associated with AngII dysfunction. Of note, the effects of AngII-inducing microglial activation go beyond blood pressure modulation. More recently, AngIIemicroglia activation has been explored in the context of vascular cognitive impairment and depression in AngII-induced hypertensive models. Depleting microglia and perivascular macrophages in this model, for instance, prevented short-term memory impairment, mainly through a decrease in the proinflammatory microglia profile and associated BBB leakage [39]. Likewise, AngII-induced hypertension has been shown to induce depressive-like behavioral despair via the action of microglia cells within the hippocampus of mice [40]. Hence, there are still several novel underlying mechanisms and a need to understand AngII-induced neuroinflammation via microglia activation as this is an interaction that affects homeostasis beyond cardiovascular regulation.

4.2 AngII and Toll-like receptors within the central nervous system In addition to microglia, Toll-like receptors (TLRs) play a vital role in the innate immune response within the CNS. TLRs are pattern recognition receptors that recognize both pathogen-associated molecular patterns and damage-associated molecular patterns. Once activated, TLRs engage downstream signaling adaptors and regulate proinflammatory responses [41]. Among the 13 characterized TLRs, TLR4 has been implicated in the development and progression of hypertension [42]. TLR4 is mainly expressed in microglial cells [43]. Hence, TLR4 has been explored within the brain as a possible underlying mechanism explaining AngII-microglial activation and neuroinflammation in cardiovascular nuclei during hypertension. In AngII-induced hypertension and SHRs, besides microglial activation within the PVN and RVLM discussed before, TLR4 gene and/or protein expression is found to be upregulated [38,44,45]. In AngII-induced hypertension, intracerebroventricular injections of a viral TLR4 inhibitory peptide ameliorate TLR4, IL-1b, TNF-a, NFkB activity, and iNOS levels in the myocardial, and circulating levels of norepinephrine. In SHRs, PVN chronic infusion of AT1R blocker decreases blood pressure, PICs, and TLR4 mRNA expression in the nuclei [46]. Finally, AngIIeAT1ReTLR4 signaling has also been implicated in microglia activation within the PVN, RVLM, and NTS, promoting neuroinflammation, baroreceptor

5. Angiotensin II and bradykinin system

impairment, autonomic dysfunction, and BBB disruption in SHRs [38]. Together, these studies support a crucial role for TLR4 via AT1R and microglial activation mediating a feed-forward prohypertensive cycle involving microglial activation, neuroinflammation, autonomic dysfunction, and BBB disruption in hypertensive models with Ang II signaling dysfunction. Another potential mechanism by which AngII produces its deleterious effects in hypertension is inducing reactive oxygen species (ROS) [47]. TLR4 signaling pathway has shown to be essential for both AngIIemicroglia activation and AngIIe ROS generation in an ex vivo approach using hypothalamic slices containing the PVN of sufficient and deficient mice treated with an exogenous application of AngII [48]. However, the role of AngIIeTLR4 microglia activation and ROS production in AngIIedysfunctional hypertensive animals remains to be determined.

5. Angiotensin II and bradykinin system Alongside AngII, the kallikreinekinin system (KKS) also plays a role in diverse pathophysiological processes by mediating inflammation. The KKS is composed of a family of vasoactive peptides involved in numerous homeostatic mechanisms, including hypertension. There are two independent systems, the plasma KKS and the tissue KKS, which both release kinins. Kinins, the key peptides in the KKS, are known for their ability to act as hormones and inflammatory mediators [49]. The formation and degradation of kinins are tightly controlled as they have diverse effects on blood vessels and various tissues. Kinins originate from circulatory glycoproteins called high- and low-molecular-weight kininogens. The highmolecular-weight kininogens are processed by plasma kallikrein to form nonapeptide bradykinin (BK, Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9), while the low-molecular-weight kininogens are processed by tissue kallikrein to form the decapeptide Lys-bradykinin or kallidin (KD, Lys1-Arg2-Pro3-Pro4-Gly5-Phe6-Ser7Pro8-Phe9-Arg10). Bradykinin and kallidin are the major kinins in mammals, and both display similar biological properties. Kinins have a short half-life in the circulation and are rapidly degraded into active and inactive metabolites by peptidases known as kininases, including ACE, neutral endopeptidase (NEP), carboxypeptidase N (CPN), and carboxypeptidase M (CPM). Kininase I-type carboxypeptidases (CPN and CPM) are key enzymes involved in the biotransformation of native kinins, by cleaving the carboxyterminal arginine from either BK or KD, giving rise to the active metabolites, des-Arg9-BK (DABK), and des-Arg10-KD (DAKD), also known as Lys-des-Arg9-BK, respectively. The kininase II-type carboxypeptidases (NEP and ACE) cleave off the C-terminal dipeptide Phe8-Arg9 from BK and KD and leads to the degradation of these peptides. Physiological effects of kinins are mediated by highly specific, G proteine coupled receptors with seven transmembrane domains, namely B1 (B1R, BDKRB1) and B2 (B2R, BDKRB2). BK and KD are relatively selective ligands for the B2R, whereas DABK and DAKD are selective ligands for the B1R. Under typical

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physiological conditions, the B2R is constitutively expressed in many tissues or organs throughout the body, whereas B1R expression is very low. However, B1R expression is induced and upregulated in the presence of cytokines and endotoxins or following tissue injury. Observations from clinical and experimental studies, including ours and others, suggest an important role for kinins and their receptors in the maintenance of normotension and the development of hypertension. Previous studies have suggested that both B1R and B2R are involved in mediating inflammation with different time courses; B2R is involved in the acute phase of inflammatory and pain response, whereas B1R is involved in the chronic phase of the inflammatory response [50]. Given the important role of B1R in mediating inflammatory response and immune cell infiltration, B1Rmediated signaling mechanisms play a role in several cardiovascular diseases, including hypertension, heart failure, stroke, diabetes, and atherosclerosis. Interestingly, there is an abundance of research evidence that points out a crosstalk between the components of RAS and KKS in mediating inflammation and hypertensive response (Fig. 14.3). ACE, which is responsible for the formation of AngII, the effector peptide of RAS, efficiently catabolizes kinins, and the affinity of ACE appears to be higher for bradykinin than for AngII. ACE inhibition is often

FIGURE 14.3 Cross-Talk Between RenineAngiotensin System and KallikreineKinin System. The angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II, can efficiently catabolize kinins bradykinin and kallidin. The angiotensin-converting enzyme 2 (ACE2) can metabolize the Des-Arg9-bradykinin and Des-Arg10-kallidin, the endogenous agonists for B1R.

6. Future perspectives

targeted as a means of antihypertensive therapy, as ACE inhibitors (ACEis) are one of the most prescribed therapeutics. It has been suggested that the beneficial effects of ACE inhibitors are, at least partly, mediated by an accumulation of kinins activating B2R leading to vasodilation. In addition, both ACE inhibitor and ARB therapies are shown to increase kinin peptide levels. On the other hand, DABK and DAKD, the active endogenous metabolites and agonists for B1R, act as a substrate for ACE2 of the RAS, the enzyme that converts AngII into Ang (1e7) [51]. We previously showed that B1R gene and protein expression were upregulated in the brain of hypertensive animals and were associated with elevated AngII levels in the brain [52]. We also demonstrated a causal relationship between B1R expression after AngII stimulation, suggesting a possible cross-talk between AT1R and B1R in mediating neuroinflammation and oxidative stress [53]. This mutual role between the different systems shows a potential interaction between both systems in hypertension. Plasma kallikrein has been shown to be involved in the activation of prorenin, the precursor to renin in the RAS, which mimics a similar role to kallikrein in the KKS. Patients with elevated plasma prorenin levels have reduced levels of prekallikrein, the kallikrein precursor, and deficiency of kallikrein, which is known as the Fletcher trait [54]. Neprilysin, a known membrane metalloendopeptidase, is an enzyme that is responsible for inactivating several angiotensin peptides (AngI, AngII) as well as bradykinin. Additionally, previous studies have suggested that B1R can dimerize, oligomerize, or heterodimerize with other GPCRs such as AT1R, AT2R, B2R, or CPM, resulting in signaling cross-talk and adding another layer of regulation to B1R signaling mechanisms. This heterodimerization between AT1R and B2R results in the increased activation of Gaq and Gai proteins. More recent studies have suggested that heterodimerization may contribute to an increased sensitivity to AngII in hypertensive women [55]. These studies clearly suggest the existence of multiple cross-talk pathways between the KKS and the RAS and indicate that these two systems are interdependent and can possibly influence the regulation of downstream signaling pathways, and thus might play a significant role in the development of hypertension.

6. Future perspectives Despite the advances in research, the mechanisms involved in the pathogenesis of human essential hypertension are multifactorial and remain unknown. Most current therapeutics target the overactive prohypertensive RAS axis. Regardless of changes in lifestyle and multidrug-based therapies, only about half of hypertensive patients have their high blood pressure under control. Target end-organ damage is a common complication of hypertension, a proven major risk factor for developing

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cardiovascular diseases, even in well-controlled hypertension. Thus, it is imperative to continue to develop effective treatments and prevention strategies to reduce the burden of hypertension. Preclinical and clinical studies suggest that hypertension is a low-grade inflammatory disease that arises due to an imbalance of the functions of mediators in two endogenous systems, the RAS and the KKS. Multidrug-resistant hypertension has been linked to exaggerated sympathetic drive and neuroinflammation, suggesting a significant ‘neurogenic component,’ hence referred to as neurogenic hypertension. In addition, the emerging evidence supports the notion that the cross-talk between the components of RAS and KKS, and/or AngII and TLR4 might be playing a pivotal role in the development and pathogenesis of neurogenic hypertension. Deciphering further interactions between AngII and other potential receptors such as B1R and TLR4 in blood pressure regulation neuroimmune mechanisms will advance our fundamental understanding of pathophysiology and provide insights for developing novel therapeutics in the future for the treatment of hypertension.

7. List of words/terms Angiotensin II, bloodebrain barrier, microglia, Toll-like receptor 4, kallikreine kinin system.

Acknowledgments Work in the authors’ laboratory is supported by funding from the NIH (SS) and the AHA (VCB). The authors have no conflicts of interest.

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Morphological aspect of the angiotensin-converting enzyme 2

15

Ken Yoshimura1, Yasuo Okada2, Shuji Toya3, Tomoichiro Asami4, Shin-ichi Iwasaki5, 6 1

Department of Dental Hygiene, The Nippon Dental University College at Niigata, Niigata, Japan; 2 Department of Pathology, School of Life Dentistry at Niigata, The Nippon Dental University, Niigata, Japan; 3Oral and Maxillofacial Surgery, The Nippon Dental University Niigata Hospital, Niigata, Japan; 4Speech-Language-Hearing Therapy, Faculty of Rehabilitation, Gunma Paz University, Takasaki Tonya-machi, Takasaki, Gunma, Japan; 5The Nippon Dental University, Chiyoda-Ku, Tokyo, Japan; 6Gumna Paz University, Takasaki City, Gunma, Japan

1. Introduction Angiotensin-converting enzyme 2 (ACE2) is a zinc metalloprotease and transmembrane glycoprotein distributed in the cell membrane and was identified from 50 sequencing of a human heart failure ventricular cDNA library [1]. This substance, also called ACEH [2], is a homolog of ACE (angiotensin-converting enzyme) [3] and has been shown to play a role as an important regulator of the renineangiotensin system (RAS) [4], a system that regulates blood pressure, fluid volume, and serum electrolytes in mammals. On the other hand, the recent global epidemics of SARS-CoV and SARS-CoV-2 coronaviruses and the vast amount of research findings in response to the resulting COVID-19 [5] have revealed a new “aspect” of the effects of ACE2 on living tissues and organs. In other words, it has been brought into focus that SARS-CoVs use ACE2 as an “anchoring tool” for entry into the host [6,7]. In addition to simply “anchoring” the SARS-CoVs to host cell membranes for fusion, it has also been found to “disrupt” the RAS, a regulatory mechanism for maintaining homeostasis, by signaling (or inhibit) intracellular signaling the ACE2 receptor. Along with this “disturbance” of the RAS, our understanding of the mechanism of intervention by medications, such as ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), is likely to be further advanced. This is expected to contribute to the enrichment of our understanding of the pathophysiology associated with this biological mechanism, such as RAAS. At the same time, immunohistochemistry-based morphological studies to identify localization of ACE2-positive cells and distribution changes have become more important due to the recent pandemic.

Angiotensin. https://doi.org/10.1016/B978-0-323-99618-1.00008-8 Copyright © 2023 Elsevier Inc. All rights reserved.

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CHAPTER 15 Morphological aspect of the angiotensin-converting enzyme 2

This chapter reviews the morphological studies of ACE2 with respect to the reported and relevant findings, including its histological localization.

2. Overview of the RAS/RAAS cascade The concept of the RAS, known as the classical pathway, is as follows (Fig. 15.1): angiotensinogen produced mainly in the liver is converted to angiotensin I (Ang I) by renin, a proteolytic enzyme secreted by the paraglomerular cells of the kidney. Ang I produces angiotensin II (Ang II) by, e.g., the pulmonary circulatory systems [8], which constricts blood vessels and contributes to a relatively “fast” increase in blood pressure. On the other hand, the concept of the renineangiotensinealdosterone system (RAAS) is as follows: Ang II induces secretion of aldosterone from the globular zone of the adrenal cortex and increases plasma potassium ion concentration by renal reabsorption. At the same time, it promotes the reabsorption of sodium ions in the renal collecting ducts, thereby contributing to the “slow” increase in blood pressure.

Increase in Plasma Na+ reabsorption enhancement K+ concentration In the Renal collecting tubule

Decrease Blood pressure Reducing glomerular afferent microvascular pressure

5$$6 Secretion

Decreased filtrate flow rate Sympathetic tension

Aldosterone

Renin secretion from the Jaxta-glomerular apparatus

Adrenal Cortex Zona glomerulosa

Renin

Angiotensinogen

5$6

Ang II

Ang I

Increase in circulating blood flow

Slow

Increase Blood pressure

Conversion

Quick Conversion in the Pulmonary circulation Arteriole contraction

FIGURE 15.1 An overview of classical pathway of renineangiotensin system (RAS) and renineangiotensinealdosterone system (RAAS). Figure was from description of Kimura F, Negoro H. Concise Text of Physiology. 8th ed. Tokyo: Nankodo; 2021. p. 173.

2. Overview of the RAS/RAAS cascade

The cascade from angiotensinogen to transmembrane G proteinecoupled receptors such as AT1, AT2, and Mas is as follows (Fig. 15.2). First, angiotensinogen (1e452) is converted to angiotensin I (1e10) by renin. Angiotensin I (1e10) is converted to angiotensin (1e9) by ACE2 (angiotensin-converting enzyme 2), while ACE (angiotensin-converting enzyme) catalyzes the rapid hydrolysis of angiotensin I to produce angiotensin II (1e8). ACE and (neutral endopeptidase, NEP) also converts the generated angiotensin (1e9) to angiotensin (1e7), while angiotensin II (1e8) is converted to angiotensin (1e7) by ACE2. Angiotensin II (1e8) is conjugated to AT1 receptors, and angiotensin (1e7) is conjugated to Mas receptors, but both angiotensin II (1e8) and angiotensin (1e7) also conjugate AT2R [8,9], and NEP converts angiotensin I (1e10) to angiotensin (1e7) [9]. Through aforementioned cascade, RAAS, including ACE and ACE2, controls the cardiovascular system and renal function as part of physiological homeostasis by maintaining blood pressure and electrolytes [10].

FIGURE 15.2 ACEs in the RAAS cascade. ACE, angiotensin converting enzyme; AT1R, Angiotensin II type I receptor; AT2R, Angiotensin II type II; ACE2, angiotensin converting enzyme 2; MasR, Mas receptor; NEP, neprilysin. Figure was from papers of Arroja M, Reid E, McCabe C, et al. Therapeutic potential of the renin angiotensin system in ischaemic stroke. Exp Transl Stroke Med 2016;8. doi:10.1186/s13231-016-0022-1. (© Arroja MMC (Licensed under CC BY 4.0). https://creativecommons.org/licenses/by/4.0/.

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3. ACE2 as a “functional receptor” during viral entry into cells ACE2 is a 120-kDa transmembrane glycoprotein of monocarboxypeptidase type I consisting of 805 amino acids. The first 17 amino acids constitutes the N-terminal signal peptide, followed by an HEXXH zinc-binding metalloproteinase motif, a C-terminal collecting domain, an insulin-like domain containing a ferredoxin-like neck domain, and finally a 22 amino acid hydrophobic transmembrane region anchored to the cell membrane [11e13] (see Fig. 15.3). This indicates that ACE2, a host membrane-bound peptidase [14], is an aspect of the so-called “functional receptor” used by the human coronaviruses SARS-CoV-1 and SARS-CoV-2 for cell entry [6,7]. Many coronaviruses utilize CD13 for cell entry, which is a cell surface glycoprotein [15,16] and is similar to ACE2 in that it is the same zinc metalloproteinase [6]. The spike protein of SARS-CoV-2 binds to ACE2 first as a receptor. The viral spike is a trimer of glycoproteins consisting of S1 and S2 subunits. The S1 subunit contains an ACE2 recognition motif in the receptor binding domain (RBD) [17]. In the mutant strain of SARS-CoV-2 that caused the global outbreak of the pandemic from October 2019 to the present, a viral spike leading to changes in binding affinity to the ACE2 protein domain (RBD) mutations [18,19] occurred, so to speaking, as an “evolution” of the virus, which also contributed to the “optimization” of the binding affinity to ACE2. On the other hand, single nucleotide polymorphisms, transcriptional variants, and posttranscriptional modifications [12,20] have been suggested to exist in the gene and protein of ACE2, which is the binding target, and may contribute to the “difference” in binding sensitivity.

6SLNHRI6$56&RY

$&(

FIGURE 15.3 A three-dimensional structure of the full-length ACE2 homodimeric protein in complex with the spike protein (RBD). RBD, receptor binding domain of spike protein of SARS-CoV-2; PD, ACE2 peptidase (PD); Neck, neck part of ACE2; TMD, transmembrane domain. Figure was from paper of Barros EP, Casalino L, Gaieb Z, Dommer AC, Wang Y, Fallon L, et al. The flexibility of ACE2 in the context of SARS-CoV-2 infection. Biophys J 2021;120(6):1072e1094. doi:10.1016/j.bpj.2020. 10.036. 2020.09.16.300459.

4. Localization of ACE2 in various tissues

4. Localization of ACE2 in various tissues It has been constructed as a comprehensive antibody-based protein expression database for expression and localization profiles in normal and cancer tissues in humans. It includes tissue images as an atlas and is searchable online at Human Protein Atlas proteinatlas.org (https://www.proteinatlas.org/) [21e23]. ACE2 protein expression has been shown in the following organs (Fig. 15.4): nasopharynx, bronchus, lung, colon, duodenum, gallbladder, kidney, adrenal gland, colon, brain, thyroid gland, oral mucosa, salivary gland, esophagus, stomach, rectum, small intestine, appendix,

FIGURE 15.4 An overview of ACE2 expression from Human Protein Atlas (proteinatlas.org) tissue expression database. *Some of the folded data visible. Created by modifying from Human Protein Atlas © Human Protein Atlas (proteinatlas.org) (Licensed under CC BY-SA 3.0). https://creativecommons.org/licenses/by/3.0/.

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liver, testis, epididymis, seminal vesicle, bladder, fallopian tube, and placenta [24,25]. In addition, detailed histochemical localization of ACE2 expression in the following organs has been reported: salivary glands such as the parotid, submandibular, and sublingual glands, oral mucosa, and associated vascular endothelium and adipose tissue [14,26], airway epithelium [27], and olfactory epithelium [28].

4.1 Liver tissue Fig. 15.5A shows HE staining of normal liver tissue and ACE2 staining by immunohistochemistry. In normal liver tissues, ACE2 has been reported to be detected not only in the epithelial lining of bile ducts and capillary bile ducts but also in some sinusoidal endothelium and periportal plexus [29]. It was reported that ACE2-positive cells were found in the cytoplasm of hepatocytes on the luminal side of interlobular bile duct cells in the portal vein region [30], and similar staining can be seen. It has also been reported that ACE2-positive cells were found in tissue macrophages, or Kupffer cells [31], which can be confirmed in arrows. On the other hand, it has been reported that ACE2-positive cells by normal liver tissue are limited to the perivascular area [32] and that the endothelial lining of the sinusoids of the liver was negative for ACE2, while occasional staining of the bile duct surface was observed, and Kupffer cells and hepatocytes were negative [33].

H-E

ACE2

FIGURE 15.5A An ACE2-positive immunohistochemical images of the liver. Arrows, Kupffer cell.

ACE2 ACE2

4. Localization of ACE2 in various tissues

FIGURE 15.5B An overview diagram of ACE2 (þ) cells in the liver.

4.2 Kidney tissue Fig. 15.6A shows HE staining and ACE2 staining by immunohistochemistry of normal kidney tissue. The tissue distribution of ACE2-positive cells in the normal kidney has been reported to be throughout the endothelium [1], while mesangial and glomerular endothelial cells are negative [33,34]. In Fig. 15.6A, a weak positive image can be seen in a localized area. Presence of localized positive cells in smooth muscle cells in medium-sized vessels [1]. Vascular endothelium has also been reported to have a clearly positive reaction [33,34], and similar stain can be observable. In addition, there was a weak positive image in the glomerulus on the visceral side [33,34], and the mural epithelial cells that make up the wall of the Bowman’s capsule were reported to have a moderately positive image [33e35], which can also be seen in Fig. 15.6A. On the other hand, the epithelial cells of the proximal tubules were also found to be positive [1,35,36], with positive images at the brush border, and similar findings were observed in Fig. 15.6A, with weak cytoplasmic staining [33,34]. It has been reported that there is a weak staining image in the cytoplasm of epithelial cells from distal tubules and collecting ducts and a positive image in endothelial and smooth muscle cells of interlobular arteries. It has also been reported that there is no positive image in the vascular endothelium of paratesticular capillaries [37].

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CHAPTER 15 Morphological aspect of the angiotensin-converting enzyme 2

H-E

ACE2

ACE2

FIGURE 15.6A An ACE2-positive immunohistochemical images of the kidney.

4.3 Pulmonary alveoli Fig. 15.7A and 15.7B shows HE and immunohistochemical images of normal lobular endobronchial lung tissue stained with ACE2, and Fig. 15.7C shows an overview of the staining. In normal lung tissue, ACE2-positive cells have been reported to react abundantly with alveolar epithelial cells, especially type II epithelial cells [33,38,39], and a moderate stain can be seen in Fig. 15.7A. It has been reported that alveolar type II cells are involved in surfactant production [39]. In addition, it has been reported that capillary endothelium also has ACE2-positive images [33], and the arrowhead in Fig. 15.7B shows a similar response. On the other hand, although some type I and type II alveolar epithelial cells were positive, most type II alveolar epithelial cells were negative for ACE2 [40], and there was no positive image of ACE2 in alveolar epithelial cells [31]. Moderate expression of ACE2 [38,40] has been reported in alveolar macrophages and dust cells [31], particularly in the cytoplasm and membrane, as indicated by the arrows in Fig. 15.7B. Moreover, monocytes in normal alveoli have been found to be ACE2 positive [37], while alveolar macrophages have been reported to lack ACE2 [39]. According to Silva et al. [41], the percentage of ACE2-positive type II epithelial cells did not differ by gender and was lower in subjects older than 60 years than in those younger than 60 years. They also reported the higher ACE2 expression among older smokers. In contrast, Faure-Bardon et al. [42] reported weak ACE2-positive image in type II epithelial cells in fetal lung tissues at 15 þ 5 weeks and a positive image only in type II

4. Localization of ACE2 in various tissues

Proximal tubular cells

Podcytes

Donoghue et a ., (2000) (Whole) endothelium ( localized) smooth muscle cells of medium-sized vessels Epithelial cells of the proximal tubule

Lely et al., (2004) Weakly positive on the visceral side in the glomerulus . Clear positive in the vascular endothelium. Negative in mesangium and glomerular endothelium. Positive in the brush border of proximal tubular cells Weak staining of cytoplasm on epithelial cells from distal tubules and collecting ducts Positive in the endothelial and smooth muscle cells in the interlobular artery. No positive reaction in the endothelium of the paratesticular capillaries.

Meiners et al., (2021) Positive in the proximal tubule. Moderately weak positive in the Bowman's capsule

Errarte et al., (2017) Positive in the proximal tubule.

Endothelial cells Glomerular visceral epithelial cell (Bowman’s capsule)

FIGURE 15.6B An overview diagram of ACE2 (þ) cells in the kidney.

epithelial cells in lung tissues from 8-year-old children. The difference in expression may be related to the age or smoking history of the subject of the observation sample.

4.4 Other tissue in the digestive system Figs. 15.8 and 15.9 shows normal pancreatic and colon tissues, and Fig. 15.10 shows ACE2 stained images of normal tongue mucosa and parotid gland tissues by immunohistochemistry.

4.4.1 Pancreas tissue It has been reported that ACE2 positivity was found on the luminal side of endothelial cells and ductal cells in normal pancreas [30]. It has been reported that ACE2 is strongly found in beta cells of pancreatic islets [37,43e45], but weak ACE2 positivity was also found in alpha and delta cells [44]. The presence of ACE2-positive pericytes scattered in or around the islet parenchyma has been reported [45,46]. In the exocrine part of the pancreas, prominent and intense staining [43,45,46] was reported for vascular components (endothelial or pericytes) found in the interatrial septum. In contrast, there is no evidence of a- or b-cells expressing ACE2 protein according to report [47].

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CHAPTER 15 Morphological aspect of the angiotensin-converting enzyme 2

H-E

ACE2

ACE2

H-E

ACE2

FIGURE 15.7A An ACE2-positive immunohistochemical images of the lung.

4.4.2 Colon tissue An et al. [30] reported that the membranes and cytoplasm of colonic tissues, especially goblet cells, were ACE2 positive, and furthermore, the luminal side of the colonic epithelium was more intense than the basal side. Hamming et al. [33] reported the presence of ACE2-positive cells in smooth muscle cells of normal colon tissue and in vascular endothelium, mucosal muscle plate, and intrinsic muscle layer, but not in intestinal cells.

4.4.3 Tongue mucosa and salivary gland In normal salivary tissues, ACE2-positive cells have been reported in the acinar region of serous glands, including the acinar epithelial cells of the parotid gland, and in both serous and mucous acinar cells of minor salivary glands, such as the sublingual, labial and buccal glands, and in the striated and intercalated ducts of all salivary glands [26,48e50]. On the other hand, reports of minor salivary glands have been observed in the cell membrane of ductal components including intralobular excretory ducts and interlobular ducts. In the submandibular gland, ACE2 expression was observed in the cell membrane/brush border of the main ducts (not shown), interlobular excretory ducts, and interlobular ducts [51]. In the submandibular gland, it has been reported that both mucous and serous gland lack ACE2 expression [51].

5. Up- and downregulation of ACE2 and related diseases

H-E

ACE2

H-E

ACE2

FIGURE 15.7B An enlarged ACE2-positive immunohistochemical images of the lung tissue. Arrows, alveolar macrophages; arrowheads, vascular endothelium.

Reactions were found in the basal and spinous layers of the oral mucosal epithelium, the basal layer [26,33,49,50,52], or the submucosal intrinsic layer [50]. ACE2 positivity was also found in the vascular endothelium of capillaries distributed in the submucosal lamina propria that nourishes the oral mucosa and salivary glands, as well as adipocytes in the lamina propria [26,49]. Taste buds in the epithelial layer of the tongue were also ACE2-positive [52]. Expression of ACE2 in gingival squamous epithelium was observed in the nuclei and cytoplasm of the spinous basal cell layer, but not in the epithelial surface and stratum corneum. The buccal surface of the gingival sulcus epithelium tended to be more strongly ACE2-positive than the buccal surface of the gingival epithelium [50].

5. Up- and downregulation of ACE2 and related diseases ACE2 is a “key factor” in the maintenance of homeostasis in organs and is known for its upregulation in organs and cellular organs, i.e., its positive regulatory effect on physiological processes at the molecular, cellular, or systemic level (NLM MeSH Description 2022: https://meshb.nlm.nih.gov/record/ui?ui¼D015854), or its increased response to substances or signals from outside the cell (NCI Dictionary:

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CHAPTER 15 Morphological aspect of the angiotensin-converting enzyme 2

Alveolar epithelial cells (type I) Fu et a ., (2020) Several positive cells

Alveolar epithelial cells (type II) Fu et a ., (2020) Some are positive, but most are negative.

Hamming et al., (2004) Abundant positive cells

Song et al., 2020 No positive reaction in the alveolar epithelial cells

Silva et al.,(2022) Percentages of ACE2-positive type II epithelial cells:. No gender differences Elderly subjects over 60 years old are lower than subjects under 60 years old ACE2 expression is higher in older smokers

Baker et al., (2021) Positive

Alveolar macrophage Fu et a ., (2020) Moderate in Cytoplasm and membrane

Song et al., 2020 Positive in the “Dust Cell”

Baker et al., (2021) Positive

Monocytes in the alveoli He et a ., (2006) Positive in several cells

Vascular endothelial cells in alveolar capillaries Hamming et al., (2004)

15+5 week fetal lung Faure-Bardon et al., (2020) Infrequently, weak positive image in type II epithelial cells.

8 years old infant lung Faure-Bardon et al., (2020) Positive only in type II epithelial cells.

Positive

FIGURE 15.7C An overview of ACE2 (þ) cells in the alveolar tissue of the lung.

https://www.cancer.gov/publications/dictionaries/cancer-terms/def/upregulation), or the process of increasing the number or activity and sensitivity of cell surface receptors and its opposite process, downregulation, which is a negative regulatory effect on physiological processes at the molecular, cellular, or systemic level (NLM MeSH Description 2022: https://meshb.nlm.nih.gov/record/ui?ui¼D015536), is responsible for tissue damage and tissue protection in various organs of the body, respectively. It is directly related to the disease and significantly affects not only the susceptibility to various diseases but also the systemic condition [53e55]. In addition, several SARS-CoV-2-related reviews [33,56e58] have suggested that binding of the SARS virus spike protein to ACE2 results in downregulation of its activity from the cell surface. The following review articles on SARS-CoV2 viral invasion and tissue damage due to ACE2 downregulation have been published: cardiac complications [59], severe cardiac damage [60], endothelial dysfunction [61], vascular thrombosis [62], lung injury [59], endothelial dysfunction [61,63,64], acute respiratory distress syndrome (ARDS) [65e67], severe lung failure [68], stroke [69e71], gastrointestinal dysfunction [72,73], prostatic hypertrophy [74], inflammation of periodontal tissue [75], multiple organ failure [76,77], macrophage activation syndrome [77], and cytokine storm [78,79]. On the other hand, the review articles on SARS-CoV-2 viral invasion related to ACE2 upregulation include the following:

5. Up- and downregulation of ACE2 and related diseases

Pancreas

H-E

H-E

ACE2

ACE2

Colon

FIGURE 15.8 An ACE2-positive immunohistochemical images of the pancreas and colon.

cardiovascular disease, hypertension [80], diabetes [80,81], hypertension [82,83], pregnancy [84], lung cancer [85], smoking [86e89], e-cigarette smoking [90], hyperglycemia [91], IFN-a [92], Th1 response [93,94], and vitamin D [95]. The following promote ACE2 upregulation in drug administration related to SARSCoV-2 treatment: ARB and MRA [96], ARB and ACEI [97], ARB and ACEI [97,98], statin [99], GLP-1R agonists [100], and glycyrrhizin [101] (Other detailed reports are also shown in Tables 15.1 and 15.2). In addition, although direct downand upregulation is not clearly demonstrated, diseases and physiological conditions that have been suggested to be associated with ACE2 include the following: renal injury [102], glomerulosclerosis (FSGS) [102e104], acute tubular necrosis (ATN) [103,104], Hartnup disorder [10], diabetic nephropathy [105], albuminuria [104], endotheliitis [103,104], idiopathic pulmonary fibrosis [102], acute lung dysfunction [102], liver fibrosis [106], primary sclerosing cholangitis (PSC) [106,107], sarcoidosis [102], Crohn’s disease [108], inflammatory bowel disease (IBD) [109], and infant and postpartum [42]. The distribution of ACE2 in salivary glands has also shown that it may be associated with xerostomia as well as a reservoir for SARSCOV-2 infection [14,110].

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CHAPTER 15 Morphological aspect of the angiotensin-converting enzyme 2

H-E

H-E

ACE2

ACE2

Tongue

Parotid gland

FIGURE 15.9 An ACE2-positive immunohistochemical images of the oral tissue.

5.1 Two axes of RAAS cascade There are a number of reviews and reports [27,111e117] that have showing that the two different “axes” in the RAAS cascade. The first “axis” is the one that promotes organizational damage. In other words, it is a cascade of conjugating AT1 receptors via Ang I and Ang II (designated Axis1 in Fig. 15.10). This cascade contributes to the promotion of inflammation, oxidative stress, vasoconstriction, fibrosis, cell proliferation, apoptosis, and hypertrophy. The other “axis” is to promote tissue protection. The cascade of Ang (1e9), Ang (1e7), AT2 receptor, and Mas receptor conjugates (labeled Axis2 in Fig. 15.10). It inhibits the aforementioned inflammation, oxidative stress, vasoconstriction, fibrosis, cell proliferation, apoptosis, and hypertrophy. These two axes are balanced and antagonistic like a balance or a seesaw, and ACE2 is involved in this balance inclination. This means that when ACE2 downregulation is promoted, it tilts the Axis1 cascade and promotes AT1 receptor conjugation. On the contrary, upregulation of ACE2 tilts the Axis2 cascade and promotes the conjugation of Mas and AT2 receptors.

5. Up- and downregulation of ACE2 and related diseases

FIGURE 15.10 Two “axes” in the RAAS cascade summarizing reviews and other publications to date. Figure was from papers of Arroja M, Reid E, McCabe C. Therapeutic potential of the renin angiotensin system in ischaemic stroke. Experimental & Translational Stroke Medicine. 2016;8. (© Arroja MMC (Licensed under CC BY 4.0)). https://creativecommons.org/licenses/by/4.0/, and Gersh FL, O’Keefe JH, Lavie CJ, Henry BM. The Renin-Angiotensin-Aldosterone System in Postmenopausal Women: The Promise of Hormone Therapy. Mayo Clinic Proceedings. 2021;96(12):3130e41.

Table 15.1 ACE2 upregulation reports. Target

Author

Reference

Condition

CoVstudy

Target species

Lung alveolar II Lung Lung (ARDS)

Ziegler et al.

[101]

In silico

Yes

hu normal

Sinha et al. Rockx et al.

[118] [119]

In silico In vivo

Yes Yes

Li et al.

[120]

In vivo

Yes

Li et al. Sinha et al.

[109] [118]

In vitro In silico

No Yes

hu ACEI mo senescent mo PM exposed rt hu ACEI

Pulmonary fibroblast PMVEC cell Kidney

Continued

403

404

CHAPTER 15 Morphological aspect of the angiotensin-converting enzyme 2

Table 15.1 ACE2 upregulation reports.dcont’d Target

Author

Reference

Condition

CoVstudy

Target species

Nephron (normal) Pancreas (embryo) Pancreas

Chen et al.

[121]

In vivo

No

mo

Wang et al.

[122]

In vivo

No

mo

Roca-Ho et al. Vaswani et al. Brosnihan et al. Goyal et al. Rouaud et al. Wong et al.

[123]

In vivo

No

mo NOD

[124]

In vivo

No

rt

[125]

In vivo

No

rt

[126] [127]

In vivo In silico

No Yes

rt hu

[128]

In vivo

No

rt T1D

[129] [123]

In vivo In vivo

No No

rt mo NOD

[118] [130] [131]

In silico In vivo In vivo

Yes No No

hu ACEI rt hu

[132]

In vivo

No

hu estrogen

[133]

In vivo

No

rt

Shao et al.

[134]

In silico

Yes

hu

Lin et al.

[135]

In vitro

No

hu

Akin et al.

[136]

In vivo

Yes

Roca-Ho et al. Song J et al.

[123]

In vivo

No

hu RAAS blocker mo NOD

[137]

In vitro

No

Wang et al.

[138]

In vitro

No

Lin et al. Burguen˜o et al. Sinha et al.

[139] [140]

In vivo In vivo

No Yes

hu shear stress hu telmisartan rt mo

[118]

In silico

Yes

hu ACEI

Placenta (normal) Pregnancy Placenta Epithelial cell Jejunal enterocytes Liver Liver Liver NASH liver Failing heart Atrial tissue Cardiac tissue Ventricular myocytes HCF fibroblast Blood Serum Endothelial cells HUVEC cell Retina Colon Intestine

Herath et al. Roca-Ho et al. Sinha et al. Zhang et al. Goulter et al. Bukowska et al. Ferraio et al.

hu, human; mo, mouse; rt, rat; ARDS, acute respiratory distress syndrome; PMVEC, pulmonary microvascular endothelial cell; NASH, nonalcoholic steatohepatitis; HCF, human cardiac Fibroblasts; HUVEC, human umbilical vein endothelial cell; ACEI, angiotensin-converting enzyme inhibitor; PM, particulate matter; NOD, nonobese diabetic; T1D, type1 diabetes; RAAS, renineangiotensin ealdosterone system.

Table 15.2 ACE2 Down-regulation reports. Author

Reference

Condition

CoV study

Target species

Lung (IPF) Lung (IPF) Acute lung injury HBEpC cell Kidney (AKI) Kidney (renal disease) Kidney (diabetic) Kidney (NGS) Kidney (high-potassium diet)v LPS-induced kidney Glomerulus tissue Glomerulus (damaged) Vero E6 cell (SARS-cov) LPS-induced HK-2 cell Pancreatic cancer (PDAC) Uterus implantation site Heart tissue Heart tissue Neonatal cardiomyocytes Myocardial tissue Atrial Aortic dissection tissue VSMC cell PASMC cell A549 cell MLE-12 cell IMR90 cell LPS-induced PMVEC cell EpH4-Ev cell Co-infection SARS-CoV

Li et al. Uhal et al. Imai et al. Zhang et al. Grigoryev et al. Reich et al. Lin et al. Wang et al. Vio et al. Bae et al. Bernardi et al. Bernardi et al. deLang et al. Bae et al. Zhou et al. Neves et al. Awwad et al. Zhao et al. Yamamuro et al. Oudit et al. Pan et al. Li et al. Li et al. Zhang et al. Uhal et al. Uhal et al. Oarhe et al. Fang et al. Wang et al. Zou et al.

[141] [142] [143] [144] [145] [144] [105] [146] [147] [148] [149] [149] [150] [148] [151] [152] [153] [154] [155] [156] [157] [158] [159] [160] [142] [142] [161] [162] [163] [164]

In In In In In In In In In In In In In In In In In In In In In In In In In In In In In In

No No No No No No No No No No No No Yes No No No No No No Yes No No No No No No No No No Yes

Hu Hu Mo hu (eendothelin) Mo Hu rt (high glucose) Hu Rt Mo rt rt (aldosterone) mnky mo hu rt rt (pregabalin) mo (TAC) rt mo prcn hu acute rt rt hu alveolar mo alveolar hu fetal lung hu mo (mammary) Mammalians (89)

vivo vivo vivo vitro silico vivo vivo vivo vivo vivo vivo vivo vitro vitro vitro vivo vivo vitro vitro vivo vivo vivo vitro vitro vitro vitro vitro vitro vitro silico

405

hu, human; mo, mouse; rt, rat; mnky, monkey; prcn, porcine; IPF, idiopathic pulmonary fibrosis; HBEpC, human bronchial epithelial cells; AKI, acute kidney injury; NGS, nodular glomerulosclerosis; LPS, lipopolysaccharide; PDAC, pancreatic ductal adenocarcinoma; VSMC, vascular smooth muscle cell; PASMC, pulmonary artery smooth muscle cell; PMVEC, pulmonary microvascular endothelial cell; TAC, transverse aortic constriction.

5. Up- and downregulation of ACE2 and related diseases

Target

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5.2 Expression of AT1, AT2, and MAS receptor The major mRNA expression organs of AGTR1, the AT1 receptor gene, are brain, thyroid, adrenal gland, lung, colon, stomach, rectum, small intestine, liver, gallbladder, pancreas, kidney, urinary bladder, reproductive organs and placenta, muscle tissues, adipose tissue, skin, etc. (Human Protein Atlas https://www.proteinatlas.org/ ENSG00000144891-AGTR1/tissue), and the major mRNA expression organs of AGTR2, the AT2 receptor gene, are adrenal gland, lung, colon, stomach, tongue, gallbladder, pancreas, kidney, reproductive organ, e.g., epididymis, cervix, endometrium, fallopian tube, heart, and smooth muscle tissues (https://www.proteinatlas. org/ENSG00000180772-AGTR2/tissue), and the Mas receptor gene, MAS1, is expressed in organs such as kidney, smooth muscle, brain, and cerebrum (https:// www.proteinatlas.org/ENSG00000130368-MAS1/tissue).

5.3 Possible (down) regulation of the ACE2 after binding the SARSCoV-2 It has been pointed out that SARS-CoV-2 may “bind” to the ACE2 receptor, thereby inducing the intracellular domain of ACE2 and disrupting the RAS-system. The quintessence of “disturbance” is the downregulation of ACE2 surface expression [102] caused by “internalization” of ACE2 through binding of the viral spike protein to ACE2. It was pointed out that the intracellular domain of ACE2 may be one of the signaling molecules that regulate cell activation, indicating that the extracellular domain (ECD) of ACE2 is “shedded” by ADAM17 and g-secretase after ACE2 interacts with SARS-CoV-2 [58]. The “shedding” of ACE2 has been shown to occur not only in SARS-CoV-2 and SARS-CoV-1, but also in other human coronaviruses such as NL63, resulting in downregulation of ACE2 [57]. On the other hand, when calmodulin, which may affect cell activation, inflammation, and cell death, interacts with transmembrane full-length ACE2, it may inhibit ACE2 shedding [165], which may maintain signal transduction, but there are still many parts that are unknown and will be shown in future studies.

6. Summary Until now, ACE2 was thought to be “just one factor” in the RAS that constitutes homeostasis in the body. However, the vast amount of research results accumulated over the past a few years to elucidate the pathogenesis and respond to the global epidemic of SARS-CoV-2, which began in 2019, have greatly expanded previous descriptions and knowledge of RAS. This has led to advances in our understanding of the RAS. Its “core” is the conflicting functions of tissue damage and reparative response by two axial cascades. It was also revealed that ACE2 contributes greatly to the pathophysiology of various diseases caused by the dysfunction of various organs in the body due to the loss of equilibrium between the two polar “axes”, and that this “equilibrium” can be greatly disturbed by viral invasion. In the future,

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tissue-specific balancing mechanisms of the two-axis cascades may be found in tissues and organs that are newly found to be ACE2 positive by immunohistochemistry. There are still many questions that remain unclear, including the details of signal induction as a “disturbance” after binding to the ACE2 receptor of SARS-CoV-2. Further studies are awaited.

Acknowledgments Declaration of COI: All authors declare that they have no conflict of interest or financial relationship relevant to this chapter to disclose. We are grateful to Mr Hitoshi Hasegawa for his excellent immunohistochemistry staining.

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[115] Silhol F, Sarlon G, Deharo J-C, Vaı¨sse B. Downregulation of ACE2 induces overstimulation of the renineangiotensin system in COVID-19: should we block the renine angiotensin system? Hypertens Res 2020;43(8):854e6. [116] Simko F, Baka T. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers: potential allies in the COVID-19 pandemic instead of a threat? Clin Sci (Lond) 2021;135(8):1009e14. [117] Chappell MC. Emerging evidence for a functional angiotensin-converting enzyme 2angiotensin-(1-7)-mas receptor Axis. Hypertension 2007;50(4):596e9. [118] Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, et al. SARSCoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 2020;181(5): 1016e1035 e19. [119] Sinha S, Cheng K, Scha¨ffer AA, Aldape K, Schiff E, Ruppin E. In vitro and in vivo identification of clinically approved drugs that modify ACE2 expression. Mol Syst Biol 2020;16(7):e9628. [120] Rockx B, Baas T, Zornetzer GA, Haagmans B, Sheahan T, Frieman M, et al. Early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection. J Virol 2009;83(14):7062e74. [121] Li Y, Zeng Z, Cao Y, Liu Y, Ping F, Liang M, et al. Angiotensin-converting enzyme 2 prevents lipopolysaccharide-induced rat acute lung injury via suppressing the ERK1/2 and NF-kB signaling pathways. Sci Rep 2016;6(1):27911. [122] Chen YW, Chenier I, Tran S, Scotcher M, Chang SY, Zhang SL. Maternal diabetes programs hypertension and kidney injury in offspring. Pediatr Nephrol 2010;25(7): 1319e29. [123] Wang L, Liang J, Leung PS. The ACE2/ang-(1-7)/mas Axis regulates the development of pancreatic endocrine cells in mouse embryos. PLoS One 2015;10(6):e0128216. [124] Roca-Ho H, Riera M, Palau V, Pascual J, Soler MJ. Characterization of ACE and ACE2 expression within different organs of the NOD mouse. Int J Mol Sci 2017;18(3). [125] Vaswani K, Chan HW, Verma P, Dekker Nitert M, Peiris HN, Wood-Bradley RJ, et al. The rat placental renin-angiotensin systemda gestational gene expression study. Reprod Biol Endocrinol 2015;13:89. [126] Brosnihan KB, Neves LA, Joyner J, Averill DB, Chappell MC, Sarao R, et al. Enhanced renal immunocytochemical expression of ANG-(1-7) and ACE2 during pregnancy. Hypertension 2003;42(4):749e53. [127] Goyal R, Yellon SM, Longo LD, Mata-Greenwood E. Placental gene expression in a rat ’model’ of placental insufficiency. Placenta 2010;31(7):568e75. [128] Rouaud F, Me´an I, Citi S. The ACE2 receptor for coronavirus entry is localized at apical cell-cell junctions of epithelial cells. Cells 2022;11(4):627. [129] Wong TP, Ho KY, Ng EK, Debnam ES, Leung PS. Upregulation of ACE2-ANG-(1-7)Mas axis in jejunal enterocytes of type 1 diabetic rats: implications for glucose transport. Am J Physiol Endocrinol Metab 2012;303(5):E669e81. [130] Herath CB, Warner FJ, Lubel JS, Dean RG, Jia Z, Lew RA, et al. Upregulation of hepatic angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) levels in experimental biliary fibrosis. J Hepatol 2007;47(3):387e95. [131] Zhang W, Li C, Liu B, Wu R, Zou N, Xu Y-Z, et al. Pioglitazone upregulates hepatic angiotensin converting enzyme 2 expression in rats with steatohepatitis. Ann Hepatol 2013;12(6):892e900.

References

[132] Goulter AB, Goddard MJ, Allen JC, Clark KL. ACE2 gene expression is up-regulated in the human failing heart. BMC Med 2004;2:19. [133] Bukowska A, Spiller L, Wolke C, Lendeckel U, Weinert S, Hoffmann J, et al. Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men. Exp Biol Med 2017;242(14):1412e23. [134] Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005;111(20):2605e10. [135] Shao X, Zhang X, Zhang R, Zhu R, Hou X, Yi W, et al. The atlas of ACE2 expression in fetal and adult human hearts reveals the potential mechanism of heart injured patients infected with SARS-CoV-2. Am J Physiol Cell Physiol 2022;322(4):C723e38. [136] Lin CS, Pan CH, Wen CH, Yang TH, Kuan TC. Regulation of angiotensin converting enzyme II by angiotensin peptides in human cardiofibroblasts. Peptides 2010;31(7): 1334e40. [137] Akin S, Schriek P, van Nieuwkoop C, Neuman RI, Meynaar I, van Helden EJ, et al. A low aldosterone/renin ratio and high soluble ACE2 associate with COVID-19 severity. J Hypertens 2022;40(3):606e14. [138] Song J, Hu B, Qu H, Wang L, Huang X, Li M, et al. Upregulation of angiotensin converting enzyme 2 by shear stress reduced inflammation and proliferation in vascular endothelial cells. Biochem Biophys Res Commun 2020;525(3):812e8. [139] Wang LJ, Ma H, Liao XX, Hu XS, Tian F, Gu HB, et al. [Study on up-regulation of the expression of angiotensin-converting enzyme-2 in human umbilical vein endothelial cells by telmisartan]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2006;18(4):224e8. [140] Lin Z, Ni Y, Hou L, Song L, Wu Y, Hu H, et al. [Telmisartan reduces retina vessel endothelial cell apoptosis via upregulating retinal ACE2-Ang-(1-7)-Mas axis in spontaneous hypertensive rats]. Zhonghua Xinxueguanbing Zazhi 2015;43(7):625e30. [141] Burguen˜o JF, Reich A, Hazime H, Quintero MA, Fernandez I, Fritsch J, et al. Expression of SARS-CoV-2 entry molecules ACE2 and TMPRSS2 in the gut of patients with IBD. Inflamm Bowel Dis 2020;26(6):797e808. [142] Li X, Molina-Molina M, Abdul-Hafez A, Uhal V, Xaubet A, Uhal BD. Angiotensin converting enzyme-2 is protective but downregulated in human and experimental lung fibrosis. Am J Physiol Lung Cell Mol Physiol 2008;295(1):L178e85. [143] Uhal BD, Dang M, Dang V, Llatos R, Cano E, Abdul-Hafez A, et al. Cell cycle dependence of ACE-2 explains downregulation in idiopathic pulmonary fibrosis. Eur Respir J 2013;42(1):198e210. [144] Grigoryev DN, Rabb H. Possible kidney-lung cross-talk in COVID-19: in silico modeling of SARS-CoV-2 infection. BMC Nephrol 2022;23(1):57. [145] Zhang H, Li Y, Zeng Y, Wu R, Ou J. Endothelin-1 downregulates angiotensin-converting enzyme-2 expression in human bronchial epithelial cells. Pharmacology 2013; 91(5e6):297e304. [146] Lin M, Gao P, Zhao T, He L, Li M, Li Y, et al. Calcitriol regulates angiotensin-converting enzyme and angiotensin converting-enzyme 2 in diabetic kidney disease. Mol Biol Rep 2016;43(5):397e406. [147] Wang M, Zhang X, Song X, Zou X, Wu W, Wang Y, et al. Nodular glomerulosclerosis and renin angiotensin system in Chinese patients with type 2 diabetes. Mol Cell Endocrinol 2016;427:92e100.

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[148] Vio CP, Gallardo P, Cespedes C, Salas D, Diaz-Elizondo J, Mendez N. Dietary potassium downregulates angiotensin-I converting enzyme, renin, and angiotensin converting enzyme 2. Front Pharmacol 2020;11:920. [149] Bae EH, Kim IJ, Choi HS, Kim HY, Kim CS, Ma SK, et al. Tumor necrosis factor aconverting enzyme inhibitor attenuates lipopolysaccharide-induced reactive oxygen species and mitogen-activated protein kinase expression in human renal proximal tubule epithelial cells. Kjpp 2018;22(2):135e43. [150] Bernardi S, Toffoli B, Zennaro C, Bossi F, Losurdo P, Michelli A, et al. Aldosterone effects on glomerular structure and function. J Renin-Angiotensin-Aldosterone Syst JRAAS 2015;16(4):730e8. [151] de Lang A, Osterhaus AD, Haagmans BL. Interferon-gamma and interleukin-4 downregulate expression of the SARS coronavirus receptor ACE2 in Vero E6 cells. Virology 2006;353(2):474e81. [152] Zhou L, Zhang R, Yao W, Wang J, Qian A, Qiao M, et al. Decreased expression of angiotensin-converting enzyme 2 in pancreatic ductal adenocarcinoma is associated with tumor progression. Tohoku J Exp Med 2009;217(2):123e31. [153] Neves LA, Stovall K, Joyner J, Valde´s G, Gallagher PE, Ferrario CM, et al. ACE2 and ANG-(1-7) in the rat uterus during early and late gestation. Am J Physiol Regul Integr Comp Physiol 2008;294(1):R151e61. [154] Awwad ZM, El-Ganainy SO, ElMallah AI, Khattab MM, El-Khatib AS. Telmisartan and captopril ameliorate pregabalin-induced heart failure in rats. Toxicology 2019; 428:152310. [155] Zhao T, Kee HJ, Kee S-J, Jeong MH. Hdac8 inhibitor alleviates Transverse aortic constriction-induced heart failure in mice by downregulating Ace1. Oxid Med Cell Longev 2022;2022:6227330. [156] Yamamuro M, Yoshimura M, Nakayama M, Abe K, Sumida H, Sugiyama S, et al. Aldosterone, but not angiotensin II, reduces angiotensin converting enzyme 2 gene expression levels in cultured neonatal rat cardiomyocytes. Circ J 2008;72(8):1346e50. [157] Oudit GY, Kassiri Z, Jiang C, Liu PP, Poutanen SM, Penninger JM, et al. SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur J Clin Invest 2009;39(7):618e25. [158] Pan C-H, Lin J-L, Lai L-P, Chen C-L, Stephen Huang SK, Lin C-S. Downregulation of angiotensin converting enzyme II is associated with pacing-induced sustained atrial fibrillation. FEBS (Fed Eur Biochem Soc) Lett 2007;581(3):526e34. [159] Li Y, Hu J, Qian H, Gu J, Meng W, Zhang EY. Novel findings: expression of angiotensin-converting enzyme and angiotensin-converting enzyme 2 in thoracic aortic dissection and aneurysm. J Renin-Angiotensin-Aldosterone Syst JRAAS 2015; 16(4):1130e4. [160] Li YH, Wang QX, Zhou JW, Chu XM, Man YL, Liu P, et al. Effects of rosuvastatin on expression of angiotensin-converting enzyme 2 after vascular balloon injury in rats. J Geriatr Cardiol 2013;10(2):151e8. [161] Zhang R, Su H, Ma X, Xu X, Liang L, Ma G, et al. MiRNA let-7b promotes the development of hypoxic pulmonary hypertension by targeting ACE2. Am J Physiol Lung Cell Mol Physiol 2019;316(3):L547e57. [162] Oarhe CI, Dang V, Dang M, Nguyen H, Gopallawa I, Gewolb IH, et al. Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts. Pediatr Res 2015;77(5):656e62.

Further reading

[163] Fang Y, Gao F, Hao J, Liu Z. microRNA-1246 mediates lipopolysaccharide-induced pulmonary endothelial cell apoptosis and acute lung injury by targeting angiotensinconverting enzyme 2. Am J Transl Res 2017;9(3):1287e96. [164] Wang K, Liu X, Xiao H, Wang H, Zhang Y. The correlation between inflammatory injury induced by LPS and RAS in EpH4-Ev cells. Int Immunopharm 2017;46:23e30. [165] Lambert DW, Clarke NE, Hooper NM, Turner AJ. Calmodulin interacts with angiotensin-converting enzyme-2 (ACE2) and inhibits shedding of its ectodomain. FEBS Lett 2008;582(2):385e90.

Further reading [1] Zou Y, Cao X, Yang B, Deng L, Xu Y, Dong S, et al. In silico infection analysis (iSFA) identified coronavirus infection and potential transmission risk in mammals. Front Mol Biosci 2022;9:831876.

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CHAPTER

The renin-angiotensin system in the eye: implications on health and disease

16

Nayara Azinheira Nobrega Cruz1, Lilian Caroline Gonc¸alves de Oliveira1, Mauro Silveira de Queiroz Campos2, Preenie de Senanayake3, a, Dulce Elena Casarini1 1

Nephrology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil; 2Ophthalmology Division, Escola Paulista de Medicina, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil; 3Cole Eye Institute, Cleveland Clinic, Cleveland, OH, United States

1. Introduction The renineangiotensin system (RAS) or renineangiotensin aldosterone system (RAAS) is one of the most studied hormonal systems since the discovery of its first component named renin, around 120 years ago [1]. RAS has a major role in regulating hemodynamic and electrolyte balance, thus controlling blood pressure [2e4]. Nonetheless, the functions of RAS are multiple and continue to expand. In the past decades, new active constituents of RAS have been discovered, and its receptors, enzymes, and peptides were identified in different organs/tissues, implying that RAS exerts local effects and participates in the pathogenesis of different diseases in multiple organs, including the eyes. Angiotensin-converting enzyme (ACE), one of the main components of RAS, was first described in the retina in 1977 [5]; thenceforth, several elements of the RAS were described in different parts of the eyes (Table 16.1) [6e26], suggesting that RAS is physiologically active and has biological functions in the eye. Additionally, disruptions of systemic and eye’s RAS are implicated in ocular diseases, such as age-related macular degeneration, retinopathy of prematurity, glaucoma, and complications of diabetes mellitus such as diabetic retinopathy [11,19,27e29]. Recently, RAS regulation has been established as an important feature of the physiopathology of COVID-19 [30], one of the greatest pandemics of the contemporary age. The receptor of SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2), which has an important role in counter regulating RAS when super activated [31,32]. COVID-19 infection can cause depletion of the local effects of a

Retired author.

Angiotensin. https://doi.org/10.1016/B978-0-323-99618-1.00015-5 Copyright © 2023 Elsevier Inc. All rights reserved.

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Table 16.1 Components of RAS in the eye. RAS component

Eye compartment

Strain

Angiotensinogen

Retina Neural retina Ciliary body Choroid Iris Vitreous

Human, Rat Human Human, Human, Human, Human,

Prorenin

Retina Ciliary body Vitreous

Human Human Human

Renin

Muller cells Vitreous Neural retina

Human, mouse, rat Human Pig Human

Retina Muller cells Ciliary body Choroid Iris Vitreous Aqueous humor

Dog, monkey, human Human Human, rabbit, porcine Rabbit, porcine Human Dog, monkey, rabbit Human Human, dog, monkey, rabbit Human

ACE

ACE2

References rabbit

Sramek et al. [6] Gerhardinger C et al. [7]

rabbit rabbit rabbit rabbit

Wagner et al. [8] Ramirez et al. [9] Wagner et al. [8] Sramek et al. [10] Danser et al. [11]

Berka et al. [12] Danser et al. [11] Danser et al. [13] Wagner J et al. [8] Vita et al. [14] Kida T et al. [15] Immonen et al. [16] Wagner et al. [8] Savaskan et al. [17] Maruichi et al. [18] Seki et al. [19]

Retina Aqueous humor Conjunctival and pterygium cell lines Cornea

Rodent Human Human Mouse Mouse

Tikellis et al. [20] Senanayake et al. [21] Holappa et al. [22] Ma et al. [23] Wang et al. [24]

Chymase

Vitreous

Human

Maruichi et al. [18]

AT1 receptor

Retina Cornea

Human Human

Savaskan et al. [17] Senanayake et al. [21]

AT2 receptor

Retina RPEeChoroid Complex

Human

Senanayake et al. [21]

MAS receptor

Retina

Human

Vaajanen et al. [25]

Ang I

Retina Choroid Vitreous Aqueous humor

Porcine Porcine Human

Danser et al. [13]

2. Human eye’s anatomy and physiology

Table 16.1 Components of RAS in the eye.dcont’d RAS component Ang II

Eye compartment

Strain

Retina Ciliary body Iris Cornea Vitreous Aqueous humor

Human, porcine, rabbit Human, rabbit Rabbit Human Porcine, human, rabbit Human, rabbit

References Danser et al. [13] Ramirez et al. [9] Senanayake et al. [21]

Ang 1e7

Aqueous humor

Human

Holappa et al. [22]

Aldosterone

Lens

Human

Hampl R et al. [26]

ACE2; this is important because diminished ACE2 expression or activity is observed in several diseases. Thus, inhibition of ACE2 biological functions can contribute to COVID-19 extrapulmonary effects, including those related to the eyes [33e36]. In this chapter, systemic and local RAS and its role in ocular health and disease will be considered.

2. Human eye’s anatomy and physiology 2.1 Primary layers

The eyes are formed by three primary layers; the outer layer is called fibrous tunic and consists of the sclera, the cornea, and their zone of interdigitation, named limbus; the middle layer is the vascular tunic which is composed of choroid, ciliary body, iris, and lens; and finally, the inner layer is the neural tunic formed by the retina [37]. Also, there are three chambers in the eyes; the posterior and anterior chambers surrounding the iris are small and filled with aqueous humor. The main chamber fills the space behind the lens up to the retina with vitreous humor and is thus called vitreous chamber (Fig. 16.1) [37].

2.2 Visual processing The visual process starts when light is conducted through the clear cornea, passing successively, pupil aperture, aqueous-filled posterior chamber, crystalline lens, and vitreous-filled chamber till reaching the retina [37]. The photoreceptors are specialized cells in the retina that receive light rays and transform them onto electrical impulses transmitted to the brain to be interpreted as vision [37]. Two types of photoreceptors exist in the human eye; the cones that enable color, precise, and central vision, and the rods that perceive black and white being responsible for vision in the dark and peripheral vision [38]. The optic nerve, located in the back of the eye, is responsible for conducting electrical impulses to the brain for interpretation [37,38].

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FIGURE 16.1 Eye anatomy, showing the three primary layers, fibrous, vascular, and nervous tunics, and their respective structures. Also, there are represented the eye’s chambers; anterior and posterior to the iris, both filled with aqueous humor, and the chamber that gives form to the ocular globe extending from behind the lens to the retina that is filled with vitreous humor.

2.3 Ocular barriers The eye is an organ protected by barriers from toxins and pathogens in the circulation [39,40]. There are two main ocular barriers: the bloodeaqueous barrier regulates exchanges between the blood and the intraocular fluids (aqueous humor and vitreous humor); it consists of the epithelium of the ciliary body, which is highly vascularized by the choroidal capillaries; the nutrients and solutes are diffused to surrounding tissues through aqueous humor [39,40]. The other barrier is the blooderetinal barrier which controls the exchange of water, ions, and molecules between the retina and the blood, and resembles bloodebrain barrier. The inner blooderetinal barrier consists of tight junctions of retinal endothelial cells, which lay on the basal lamina composed of astrocytes and Muller cells [39,40]. The outer blooderetinal barrier is composed of tight junctions between neighboring retinal pigmented epithelial cells [39,40].

2.4 Ocular blood flow regulation Ocular blood flow is relatively constant due to autoregulation, only varying upon eye metabolic demand (retinal activity and thermoregulation); while extraocular vessels are controlled by vasoactive molecules released by endothelial cells, retinal vessels

3. Renineangiotensin system

are additionally influenced by neural and glial cells; noteworthy, due to the bloode retinal barrier, circulating hormones including endothelin I and angiotensin (Ang) II have no potential effect on retinal vascular resistance [41,42]. Conversely, in choroid vessels, the capillaries are fenestrated, and larger molecules including hormones can directly access smooth muscle cells causing vasodilation or vasoconstriction [41,42].

2.5 Aqueous humor homeostasis and intraocular pressure The normal function of the eye depends on fluid homeostasis as the imbalance between the production and outflow of aqueous humor can result in its accumulation inside the eye, thus increasing intraocular pressure (IOP). In the human eye, aqueous humor is secreted from the non-pigmented ciliary epithelial cells in the posterior chamber at a rate of 2.5e2.8 mL/min and then flows to the anterior chamber through the pupil; from there, the majority of aqueous humor, around 90%, is drained out through trabecular meshwork into the Schlemm’s canal, and the remaining 10% flows out via the uveoscleral pathway (Fig. 16.2A and B) [43e45]. Also, lymphatic vessels are known to be important in interstitial fluid homeostasis and immunosurveillance; however, only recently, advances in imaging and molecular techniques allowed the identification of a rich network of lymphatic vessels in the conjunctiva, proposed as a putative route for aqueous humor drainage [46]. The formation of aqueous humor involves three distinct processes: active secretion, diffusion from the blood, and ultrafiltration [43,47]. Active secretion is the main responsible for aqueous humor formation, accounting for up to 90% of aqueous humor production. It depends on the active transport of anions, cations, and water across a concentration and osmotic gradient in bloodeaqueous barrier, which is mediated by protein transporters and water channels named aquaporins [43,48,49]. Aqueous humor has in its composition electrolytes, inorganic and organic solutes, growth factors, proteins, enzymes, amino acids, and cytokines that allow the maintenance of eye homeostasis [43,50,51]. Several physiological mechanisms are involved in the regulation of IOP, including autonomic regulation and the effects of prostaglandins, serotonin, dopamine, adenosine, corticosteroids, cannabinoids, and angiotensins, which can act regulating choroidal blood flow, stimulating or inhibiting aqueous humor production, modulating contractility and relaxation of ciliary smooth muscle and/or trabecular meshwork cells, and modulating uveoscleral outflow [52e54].

3. Renineangiotensin system The RAS is a major physiological system regulating blood pressure and fluid electrolyte homeostasis. This system has been extensively studied since the discovery of the first component, renin, by Robert Tigerstedt and Per Bergman [1]. Renin was described as a component secreted by the kidneys and capable of raising renal blood pressure [4]; posteriorly, Kohlstaedt et al. [55] characterized renin as an enzyme,

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CHAPTER 16 Renin-angiotensin system in the eye

FIGURE 16.2 Aqueous humor drainage in healthy eyes through the trabecular meshwork pathway (blue arrows) and uveoscleral pathway (pink arrows) is demonstrated in the upper panel. In the bottom are schematized defects in aqueous drainage which contribute to raising intraocular pressure (IOP). In the bottom left panel, there is resistance of trabecular meshwork comp romising aqueous humor drainage through this route, and then aqueous humor builds up in the anterior chamber slowly raising IOP; this alteration is frequently seen in open-angle gl aucoma. In the bottom right panel, the aqueous humor accumulates in the posterior chamb er pushing the iris forward; this movement causes an angle closure in which the iris blocks the trabecular meshwork (TMP) and the uveoscleral pathway, and the aqueous humor acc umulates inside the anterior chamber, IOP rises rapidly causing angle-closure glaucoma.

contributing to the hypothesis that products of renin were the true agents contributing to blood pressure rise. In 1940, two distinct research groups led by BraunMene´ndez and Irvine Page simultaneously identified the angiotensin peptide, a

3. Renineangiotensin system

product of renin activity [56,57]. Later, Skeggs et al. [58] described two forms of angiotensin, and the peptides were named angiotensin I (Ang I) and angiotensin II (Ang II). In 1956, Skeggs et al. [59] characterized ACE and had shown its enzymatic action converting Ang I into Ang II. Historically, these are the pillar discoveries which led to the birth of RAS, and subsequent research rapidly accumulated information and led to our current understanding of the expanded complex RAS and functions (Fig. 16.3A and B). It is well recognized that renin represents the first and the rate-limiting step of the RAS cascade. The enzyme is an aspartyl protease able to cleave the angiotensinogen (AGT), an a-glycoprotein, to form Ang I [60,61]. The AGT is released mainly by the liver, but heart, kidney, and adipose tissue are also sources of AGT [62]. Renin is synthesized in the kidneys as a truncated protein called prorenin, which can be activated by cathepsin B, kallikrein, trypsin, or plasmin or by nonproteolytic pathways including acid pH and low temperatures; noteworthy, prorenin is present in the plasma in 10-fold greater concentrations than renin [35,61,63]. Renin secretion is mediated by the juxtaglomerular cells in the kidneys and has complex regulation; however, the main stimulus are a decrease in chloride concentration in renal tubules that is sensed by specialized cells in the macula densa, depletion of plasma volume, and sympathetic nervous discharge to the kidneys [61,64e66]. The premise of renin being only an enzyme-generating Ang I and of prorenin being only an inactive proenzyme was contested after the discovery of a (pro)renin receptor ((P)RR) in 2002 [61,66]. It was shown that renin and prorenin can act as hormones; their binding to (P)RR triggers intracellular mechanisms involved in the development of fibrosis and hypertrophy. Additionally, renin bound to (P)RR has increased catalytic efficiency, and prorenin becomes active, thus upregulating Ang I-generating activity and promoting RAS activation [61,67,68]. ACE is described in many tissues and cells, including lung, kidney, intestine, placenta, pancreas, adrenal, choroid plexus, and eye. ACE is also expressed in biological fluids, e.g., plasma, urine, and ileal fluid [8,14,16,33,34,69e76]. Ang I is cleaved by ACE to generate Ang II; this comprises the classic pathway for Ang II generation [77]. Classical Ang II effects are mediated by binding to the angiotensin II receptor type 1 (AT1R), which is abundantly present in the human tissues, promotes vasoconstriction, and stimulates the release of aldosterone by adrenal gland and vasopressin by neurohypophysis, promoting the reabsorption of sodium and water by the kidneys, hence raising blood pressure [77e79]. Additionally, Ang II binding to AT1R triggers proinflammatory, prooxidant, proangiogenic, and antiapoptotic effects at intracellular level [80,81]. The angiotensin II receptor type 2 (AT2R) has opposite effects to AT1R promoting vasodilation, apoptosis, antifibrotic, antiangiogenic, antiremodeling, and antioxidant responses upon Ang II binding [78,79,82]. However, AT2R expression in adult tissues is low, as it is more abundant during fetal development and in reproductive organs in adults [83]. Blockage of Ang II is targeted in antihypertensive therapy; clinically effective agents are ACE inhibitors (ACEIs) (such as captopril, enalapril, ramipril, and lisinopril) and AT1R blockers (ARBs) (such as losartan, valsartan, candesartan, and

425

FIGURE 16.3 The renineangiotensin system (A) The three types of pathways are represented with different patterns of arrows. The precursor AGT is processed by renin, releasing Ang I, which can be cleaved by ACE to form Ang II. Prorenin can be converted to renin by proteolytic or nonproteolytic activation. The main function of ACE2 is to cleave Ang II to form Ang 1e7, representing an axis that counterbalances the harmful effects of Ang II. Several enzymes such as tonin, trypsin, kallikrein, cathepsin G, and chymase can produce Ang II directly from AGT or from Ang I. ACE2 can cleave Ang I to form Ang 1e9; this cleavage can also be promoted by carboxypeptidase A or cathepsin A. Ang 1e9 can be further converted to Ang 1e7 by ACE or neprilysin. Ang 1e12, the peptide, is formed from the cleavage of AGT by kallikrein. Ang 1e12 is an alternative Ang II-forming substrate used by chymase. The metabolism of Ang II by aminopeptidases generates the active peptides Ang III and Ang IV. The Ang III can be generated from Ang 2e10 cleaved by ACE or from Ang II by the activity of aminopeptidase A; Ang III can be further metabolized to Ang IV by aminopeptidases N, M, and B. As an alternative axis of RAS composed of new active peptides Ang A/alamandine, Ang A is a metabolite of Ang II generated by the action of an aspartate decarboxylase. The alamandine can be formed from Ang A being cleaved by ACE2 or by decarboxylation of Ang 1e7 aspartate residue. (B) Schematic representation of angiotensins and their receptors, as well as the consequent effect of each interaction. ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; AGT, angiotensinogen; Ang, angiotensin; AT1R, angiotensin II receptor type 1; AT2R, angiotensin II receptor type 2; AT4R, angiotensin II receptor type 4; MRGD, Mas-related G proteinecoupled receptor member D; NEP, neprily sin; (P)RR, (pro)renin receptor; RAS, renineangiotensin system.

3. Renineangiotensin system

telmisartan) are commonly used [35,84]. Inhibition of ACE is particularly successful because the enzyme is a pivotal cross-link point between RAS and kallikreinekinin system (KKS), an important hormonal system also involved in blood pressure regulation; in KKS, ACE inactivates bradykinin, a potent vasodilator [35,85]. Moreover, it is proposed that ACEI and ARBs upregulate the counterregulatory axis of RAS composed of ACE2/Ang 1e7/Mas [84,86e88]. ACE2 is a zinc metallopeptidase that cleaves a single amino acid from the carboxy-terminal of its substrates; it was discovered by two distinct groups almost 50 years after the discovery of its homolog ACE [61,89,90]. In RAS, the main function of ACE2 is to cleave Ang II to form Ang 1e7, an endogenous regulator of Ang II and AT1R deleterious effects. Ang 1-7 binds to its receptor Mas and promotes vasodilation, diuresis, natriuresis, anti-inflammatory, antioxidant, and antifibrotic actions [91]. Besides classical and counterregulatory axes of RAS, there are still alternative pathways for the formation and inactivation of Ang II, Ang 1e7, and other active peptides. Several enzymes such as tonin, trypsin, kallikrein, cathepsin G, and chymase can produce Ang II directly from AGT or from Ang I under physiological and pathological conditions [92e97]. ACE2 can cleave Ang I to form Ang 1e9; this cleavage can also be promoted by carboxypeptidase A or cathepsin A. Ang 1e9 binds to AT2R upregulating nitric oxide biosynthesis and bradykinin effect, thus reducing blood pressure [98e100]. Ang 1e9 can be further converted to Ang 1e7 by ACE or neprilysin (NEP) [101e103]. A renin independent angiotensin, Ang 1e12, was discovered in 2006 in rat intestine. Ang 1e12 is formed from the cleavage of AGT by kallikrein [104]. Ang 1e12 is an alternative Ang II-forming substrate used by chymase, and its concentration is increased in primary hypertension [105,106]. The metabolism of Ang II by aminopeptidases generates the active peptides Ang III and Ang IV, the main effectors of local RAS in the brain. The Ang III can be generated from Ang 2e10 cleaved by ACE or from Ang II by the activity of aminopeptidase A; most Ang II in the brain is rapidly converted into Ang III by aminopeptidase A, and Ang III binds to AT1R and AT2R modulating the central response on blood pressure control [107,108]. Ang III can be further metabolized to Ang IV by aminopeptidases N, M, and B [102,103]. Ang IV can mediate vasopressor response acting on AT1R; however, Ang IV acts preferentially on angiotensin II receptor type 4 (AT4R), whose actions are related to the improvement of cognitive functions, such as learning and memory [109,110]. Recently, an alternative axis of the RAS composed of the new active peptides Ang A/alamandine/MrgD was discovered [111e113]. Ang A is a metabolite of Ang II generated by the action of an aspartate decarboxylase, Ang A interacts with AT1R and AT2R and promotes effects similar to Ang II but with lower potency [111,113]. Alamandine differs from Ang 1e7 by an alanine instead of an aspartate residue in the N-terminal. It is postulated that alamandine can be formed from Ang A being cleaved by ACE2 or by decarboxylation of Ang 1e7 aspartate residue [111,113]. Alamandine has vasodilator, antihypertrophy, and antifibrotic actions

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counteracting Ang A and Ang II [112,114,115]. Alamandine’s effects are mediated by the Mas-related G proteinecoupled receptor member D (MrgD) [112,113]. As seen, RAS is a complex system with several active peptides, intrinsic regulation, and requires the interaction of multiple organs to compose the systemic RAS involved in the regulation of extracellular fluid homeostasis and blood pressure. Nonetheless, RAS functions go far beyond, as there is evidence of a local RAS in multiple organs/tissues exerting paracrine, intracrine, and autocrine effects, whose regulation can be independent of systemic RAS [70,116,117]. Impairment in local RAS is observed in a wide range of diseases, including ocular disorders, as is aborded in the next sections [70,116e118].

4. Local renineangiotensin system in the eye The concept of the presence and importance of local RAS started to be debated in 1971 after the discovery of renin in dog brain [119]. Currently, it is established that some organs contain a fully operating RAS that can exert functions independently or interact with circulating RAS [70,79,120]. Since Igic et al. [5] described ACE activity in homogenate derived from retina; the main components of RAS including renin, prorenin, components of the classical axis, ACE/Ang II/AT1R, and the counterregulatory axis, ACE2/Ang 1e7/Mas receptor, were identified in different structures of the eyes in diverse species (Table 16.1). However, there are some knowledge gaps concerning ocular RAS, and its function is yet to be clarified. It is not clear if angiotensin hormones present in the eye are the product of local RAS activity or from circulation, but considering that Ang II and Ang 1e7 are found in the aqueous and vitreous humor, it is plausible that they are locally formed, as the exchange of ions, nutrients, hormones, and molecules between these fluids and blood circulation is controlled by bloodeaqueous barrier [9,13,17,21,22,25,39]. Additionally, ocular blood flow is self-regulated, and exposure of retinal vessels to circulating vasoactive substances is restricted by blooderetinal barrier [40]. Furthermore, evidence in favor of independent local RAS in eyes is that levels of Ang I and Ang II are up to 100-fold higher than in plasma [13]. ACE activity is also shown to be augmented in rabbits’ eyes in comparison with plasma [9]. AT1R, AT2R, Mas, and their agonists Ang II and Ang 1e7 are expressed locally in retina and may be involved in the regulation of retinal vascular resistance, thus participating in the control of blood flow, which should adapt to retina’s metabolic demand to ensure visual function [13,17,21,25]. Additionally, RAS may modulate ocular blood flow indirectly by regulating nitric oxide synthesis, bradykinin degradation, and prostaglandin metabolism, all important vasoactive substances in ocular vascular beds [121e123]. RAS has a putative function on aqueous humor drainage, an essential feature to avoid the rise of IOP; treatments with ACEI, ARBs, and renin inhibitors can enhance aqueous humor outflow, reducing IOP [22,124e128]. Moreover, Ang II acts as a secretagogue in nonpigmented epithelial cells from ciliary body contributing to cell volume loss, the effect is mediated by AT1R [129].

5. Eye diseases and the local renineangiotensin system

Understanding local RAS regulation and biological functions in the eyes is necessary; once, an imbalance of two main axes of RAS, ACE/Ang II/AT1R and ACE2/Ang 1e7/Mas receptor, is frequently described in different structures of the eye, in many pathological conditions, such as glaucoma, retinopathy of prematurity (ROP), age-related macular degeneration, diabetic retinopathy (DR), ocular inflammation, and ophthalmic manifestations of COVID-19 [118,130e134]. Thus, the RAS could be considered as a potential therapeutical target in ocular disorders.

5. Eye diseases and the local renineangiotensin system 5.1 Glaucoma

Glaucoma is the third leading cause of vision loss and the second leading cause of blindness following cataract and trachoma; however, considering the causes of irreversible blindness, glaucoma is the leader [135,136]. The glaucomas are a group of neurodegenerative diseases affecting retinal ganglion cells, which are neurons that have their cell bodies in the inner retina, and their axons projected to the optic nerve [118,137]. In 2020, 80 million people had glaucoma worldwide, and the forecast is that in 2040 this group will add up to 111.5 million according to the World Health Organization (WHO). Glaucoma can remain asymptomatic during its evolution being detected only when the optical nerve is severely damaged [137]. Currently available therapies cannot reverse glaucomatous damage; however, early diagnosis and treatment can efficiently arrest disease progression [136,138]. The pathogenesis of glaucoma is not fully understood, but high IOP is the most evident mechanism involved in glaucoma progression, although many glaucomatous patients have normal IOP and still present vision loss [137,138] (Fig. 16.4). Other factors may be involved in onset and progression of glaucoma, such as impaired ocular blood flow, structural modifications of the lamina cribrosa, low intracranial pressure, autoimmunity, and mitochondrial dysfunction [138]. Moreover, there are risk factors that can be linked to glaucoma such as advanced age, family history, use of systemic or topical corticosteroids, diabetes, vascular dysfunction, and systemic hypertension [137,139,140]. There are two broad categories of glaucoma, open-angle glaucoma and angleclosure glaucoma (Fig. 16.2), which can be further divided into primary, when no identifiable systemic or ocular disorder accounts for glaucoma, or secondary, when there is a primary cause leading to glaucoma, such as trauma, inflammation, advanced cataract, alteration of pigments inside the eyes, hemorrhage, tumors, and obstruction of intraocular vessels. Rarely, glaucoma can be originated from eye development disorders being classified as congenital glaucoma [137,138]. Primary open-angle glaucoma is harder to diagnose as the disease can progress silently for several years with a gradual rise in IOP until optic nerve damage and peripheral visual field changes manifest [136,141,142]. Conversely, in closed-angle glaucoma, disorders of the iris, the lens, and retrolenticular structures contribute

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FIGURE 16.4 Schematic representation of the development and effects of glaucoma. The most evident mechanism involved in its progression is increased intraocular pressure (IOP) commonly due to humor aqueous build-up and dissipation (blue arrows). White arrows indicate the pressure exerted on the eye’s structures, retina, lens, and anterior chamber. The squares in the right highlight a comparison between the optic disc and optic nerve of a healthy eye and of a glaucomatous eye, in which the optical disc is pressed forming a depression (optic cup) that enters the optic nerve damaging it.

to the blockage of aqueous humor flow from the posterior chamber to the anterior chamber through the pupil [137]. Aqueous humor accumulates behind the iris causing angle-closure glaucoma (Fig. 16.2), severe headache, intense ocular pain, and sudden rise in IOP that damages the optic nerve and causes acute vision loss. Closure-angle glaucoma is an emergency, which must be treated quickly, as it can lead to partial or even total visual loss [136,137,143]. Current pharmacotherapy to prevent the onset of glaucoma or restrain its progression consists in drugs that diminish aqueous humor formation or increase its drainage, thus reducing IOP [144]. Drugs capable of reducing neuroinflammation and preventing retinal ganglion cell death would be also beneficial [118,144]. There is cumulative evidence that antihypertensive drugs blocking RAS (ARBs, ACEI, and renin inhibitors) ameliorate glaucoma in animal models [124e128]. The exact mechanism of action is not clarified but involves the reduction of IOP [44,145]. Ang II is shown to increase cytoplasmatic sodium in non-pigmented ciliary epithelium by activating Naþ/Hþ transporter, which may impair aqueous humor

5. Eye diseases and the local renineangiotensin system

formation [146]. In bovine trabecular meshwork cells, Ang II induces proliferation and collagen deposition, which could compromise aqueous humor drainage through this pathway [44,147]. Ang II also interferes in the uveoscleral pathway decreasing the flow through this route [127]. Blockage of these Ang II effects may contribute to the ocular antihypertensive effects of ARBs and ACEI. Furthermore, ACEI effects may be mediated by inhibition of bradykinin breakdown, which stimulates nitric oxide and prostaglandins synthesis, both regulators of ocular blood flow, prostaglandins also improve uveoscleral outflow [121,123,148]. In addition, agonists of the ACE2/Ang 1e7/Mas receptor axis in ocular tissues consist in a promising pharmacological class to manage glaucoma [149]. Intravitreal administration of Ang 1e7 reduces IOP; the effect is mediated by Mas activation and may be related to aqueous humor production, as no effects were observed in outflow studies [150]. Moreover, the ACE2 activator diminazene aceturate (DIZE) enhances ACE2 expression and Ang 1e7 synthesis in the retina, reverses ocular hypertension induced by hyaluronic acid injections, promotes aqueous humor drainage in the anterior chamber, and prevents retinal ganglion cell death by apoptosis [151]. The neuroprotective effects of DIZE preserving ganglion cell loss are also observed with captopril, telmisartan, and candesartan which may enhance ACE2 expression in ocular tissues, as some ACEI and ARBs have been reported to do in cardiac tissue [84,86e88,152,153].

5.2 Diabetic retinopathy Diabetes mellitus (DM) is a term for heterogeneous metabolic disorders that culminate in chronic hyperglycemia. This occurs when the organism has absent or insufficient insulin biosynthesis or cannot effectively use the insulin produced [154]. The prevalence of DM has steadily increased in developed and developing countries and has become a public health issue as chronic hyperglycemia leads to serious damage to the heart, kidneys, blood vessels, nerves, and eyes [155]. Diabetic retinopathy is one of the main microvascular complications of DM being a major cause of blindness in the US working population [156]. DR is detected in most patients with type 1 DM and in approximately 60% of patients suffering from type 2 DM [157]. Other contributors to DR development include high blood pressure, hyperlipidemia, age, and oxidative stress [157]. Clinically, the characteristic lesions and changes of DR affect the microvasculature of the retina, precisely in the inner blooderetinal barrier consisting in loss of pericytes, augmented sinuosity of capillaries, microaneurysms, and capillary obliteration [158,159]. More severe lesions include retinal neovascularization, which defines the proliferative DR, and leakage of plasma proteins from damaged vessels, leading to diabetic macular edema [157,158]. Progression of DR compromises the retina, leading to longterm vision loss. The exact mechanisms by which hyperglycemia promotes the onset and progression of DR are yet to be elucidated, but it is known that common metabolic pathways to handle excess glucose culminate in the formation of deleterious subproducts such

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as sorbitol, protein kinase C (PKC), and advanced glycosylation end products that impair osmotic gradient and promote oxidation, inflammation, proliferation, and angiogenesis in retinal cells [160e162]. Moreover, hemodynamic alterations placed during hypertension contribute to retinopathy by increasing sheer and stretch stress and by promoting endothelial dysfunction [163]. In addition, the impairment in RAS system frequently observed in arterial hypertension plays a role in the pathogenesis of DR [164]. RAS components are at elevated levels in the blood and eyes of patients with DR and in animal experimental models of diabetes, suggesting that this system is implicated in DR pathogenesis [125e127]. Ang II mediates the effects of RAS in DR by activating PKC, inducing angiogenesis, and consequently promoting neovascularization in retina [165]; moreover, Ang II activates NFkB inflammatory cascade in retinal cells [166]. Blocking RAS with ARBs and ACEI in individuals suffering from DM is beneficial either preventing DR or restraining its progression [156]. Treatment of DM type 1 patients with losartan or enalapril reduced the odds of DR progression in two or more steps by 65% and 70%, respectively [164]. Candesartan prevents the onset of DR in individuals with DM type 1 and is shown to reduce the risk of retinal microaneurysm score progression in patients with DM type 1 and type 2 [167,168]. Finally, captopril and lisinopril restrain DR progression but do not reduce its incidence [156,169]. Also, prorenin and (P)RR are overexpressed in diabetic vitreous humor and retina, and prorenin signaling was shown to promote leukocyte adhesion in retinal cells and to induce angiogenesis through vascular endothelial growth factor (VEGF) stimulation [11,132,170,171]. Blocking of (P)RR blunts these effects and consists in a candidate therapy for treating DR [171]. Also, enhancement of ACE2/Ang 1e7/Mas receptor locally has been tested as a potential therapeutical mechanism slowing DR progression. Delivery of ACE2 and Ang 1e7 in the retina of diabetic mice using an adenovirus vector reduces vascular leakage, macrophage infiltration, formation of acellular capillaries, oxidative stress, and retinal basement membrane thickening [172]. Noteworthy, systemic control of RAS is as much important as the local effects of anti-RAS therapy for DR. Poor glycemic control, nontreated hypertension, and dyslipidemia are known to worsen DR; systemic control of RAS improves metabolic profile in general, contributing to DR prevention and management in diabetic individuals [173e175].

5.3 Age-related macular degeneration Age-related macular degeneration (AMD) is an age degenerative disease that compromises central vision by damaging a specific region in the center of the retina named macula, which contains a high density of photoreceptors; AMD is the most common cause of vision loss in elders [176]. Accumulation of drusen, yellow deposits formed by lipids and proteins under the retina is a hallmark to define the risk of developing AMD and to classify AMD into early, intermediate, or advanced. The

5. Eye diseases and the local renineangiotensin system

advanced AMD can be further classified into non-neovascular AMD (synonym of dry, atrophic, and nonexudative AMD) and neovascular AMD, also known as wet or exudative AMD [176e178]. Advanced non-neovascular AMD is the most common form of AMD accounting for around 90% of the cases. Besides the drusen, there is geographic atrophy extending to the macula; the progression is gradual and may lead to visual loss in a few decades [177]. Neovascular AMD comprehends less than 10% of the cases of advanced AMD; it is characterized by choroidal neovascularization; the abnormal blood vessels can break down bloodeaqueous barrier and cause hemorrhages, leading to vision loss [176,177]. Characteristics such as advanced age, presence of arterial hypertension, history of smoking, obesity, white race, and genetic and environmental factors are risk factors associated with AMD [178]. The imbalance of RAS is related to AMD, firstly because this is a common feature in systemic hypertension, one of the main risk factors for AMD development. Also, Ang II modulates retinal pigmented epithelium metabolic activity; impairment of RAS may cause dysfunction of the tissue and photoreceptors [179]. Additionally, Ang II has mitogenic effects in retinal endothelial cells possibly contributing to choroidal neovascularization [179]; in concordance, pretreatment with losartan and imidapril reduces choroidal neovascularization induced by laser photocoagulation in an experimental model of neovascular AMD [180,181]. Similar to DR treatment, agents with antiangiogenic, anti-inflammatory, and antioxidant properties targeting the retina and choroid may have positive effects in individuals suffering from AMD; then, ARBs, ACEI, (P)RR blockers, and ACE2/Ang 1e7/Mas receptor enhancers are considerable therapies [132,171,172,181]. Indeed, hypertensive patients treated for long-term with RAS blockers are less prone to develop geographic atrophy and soft drusen; they also have a lower risk of presenting early and advanced AMD [182].

5.4 Retinopathy of prematurity Retinopathy of prematurity (ROP) is a vasoproliferative disease secondary to inadequate vascularization of the immature retina of premature newborns, which can lead to blindness or severe visual sequelae [183]. ROP is one of the main causes of blindness in children; however, it is preventable if adequate neonatal care is provided, as a consequence of the prevalence of blindness provoked by ROP is discrepant among developing and developed countries [183]. All risk factors associated with ROP involve birth with premature retina development: lower gestational age (born Ang (1e7) > Ang (1e9)) [97]. Similar to the systemic action of Ang II, the Ang III causes an increase in blood pressure, aldosterone release, vasopressin, and atrial natriuretic peptide release [98]. Despite numerous reports on the important function of AT2R, the effect of Ang III on adipocytes is poorly understood. The Ang III can enhance glucose uptake in 3T3-L1 adipocytes by further increasing adiponectin secretion to induce the expression of GLUT1 or GLUT4 [99]. The use of a specific antagonist of AT2R demonstrated that the stimulatory effect of Ang III was mediated by AT2R, suggesting that Ang III locally produced from Ang II might act as an autocrine and/or paracrine

4. Additional angiotensins

FIGURE 25.4 Additional angiotensin peptides in WAT. Alamandine is formed from decarboxylation of Ang (1e7), and binds to MrgD, thus inhibiting leptin expression and increasing PAI-1 expression, which leads to inflammation. Beyond that, Ang II can be cleaved by APA and form Ang III. Ang III is the most potent endogenous AT2R agonist, leading to GLUT4 and adiponectin expression, hence improving glucose uptake and inhibiting inflammation. Additionally, Ang III can also bind to AT1R, where it will promote PAI-1 expression. APN acts on Ang III and forms Ang IV. Although Ang IV has a very weak affinity with AT1R and AT2R, it binds to AT4R (predominant). AT4R is a binding site at IRAP, which is mainly present in cytosolic vesicles, and translocates to the plasma membrane upon insulin stimulation. IRAP activity is inhibited by Ang IV, thus reducing inflammation. Ang, angiotensin; APA, aminopeptidase A; APN, aminopeptidase N; AT1R, angiotensin type 1 receptor; AT2R, angiotensin type 2 receptor; AT4R, angiotensin type 4 receptor; GLUT, glucose transporter; IRAP, insulin-regulated aminopeptidase; MrgD, MAS-related G proteinecoupled receptor D; PAI-1, plasminogen activator inhibitor 1.

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CHAPTER 25 Angiotensins in obesity: focus on white adipose tissue

hormone to modulate glucose uptake by adipocytes [99]. Furthermore, previous studies have reported that body weight changes increase APA activity in the systemic circulation, which suggests the role of WAT in this process, in both ob/ob obese mice [100] and obese Zucker rats [101] (Fig. 25.4). As a result of increased APA activity, the Ang III/AT2R arm is activated and enhances natriuresis as a part of a compensatory response to metabolic disturbances observed in obese individuals. On the other hand, some studies have demonstrated that Ang III can also increase the release of plasminogen activator inhibitor (PAI)-1, a key component of fibrinolysis involved in WAT expansion and insulin resistance, in human adipocytes from mammary adipose tissue (103) and from subcutaneous adipose tissue (104). Further studies need to be performed to better understand the role of Ang III in WAT.

4.2 Ang IV or Ang (3e8) Ang III can be further processed to Ang IV by aminopeptidase N (APN) or, alternatively, it can be also hydrolyzed from Ang II by dipeptidyl aminopeptidase III (DPP3) [94]. This hexapeptide was initially considered biologically inactive because it has a very weak affinity with AT1R and AT2R. However, subsequently, it was found that Ang IV is effective for correcting memory deficits in animals with amnesia via stimulation of AT4R, a newly discovered receptor that specifically binds to Ang IV with high affinity [93]. Actually, AT4R is a binding site at insulinregulated aminopeptidase (IRAP), a member of the M1 aminopeptidase family. IRAP is predominantly present in cytosolic vesicles together with GLUT4, from where they translocate to the plasma membrane upon insulin stimulation [93]. Then, IRAP is involved in glucose uptake by GLUT4, and its activity is completely inhibited by AT4R agonists, such as Ang IV [23]. Currently, it is unclear whether Ang IV acts as an exclusive agonist for the putative AT4R alone or as a partial but active agonist for the AT1R [102] and AT2R [103]. Although mainly concentrated in the brain, AT4R is distributed in a wide range of tissues including heart, blood vessels, kidney, lungs, and adipose tissue [93]. Recently, the Ang IV/AT4R arm has been recognized to play an important role in antagonizing the effect of Ang II, mainly in hearts [104] and diabetic cardiomyopathy [105]. Ang IV/AT4R arm activation plays a systemic role in the regulation of glucose homeostasis and inflammatory processes and in the metabolism of various hormones including vasopressin, oxytocin, and somatostatin [106]. The AT4R-binding site seems to be one of the predominant receptors in adipose cells and local concentrations of Ang II, and their degradation products may be extremely elevated in adipose tissue [107]. Alponti et al. showed that obesity is associated with dysregulation of IRAP activity in adipose tissue along with impaired insulin-regulated traffic of IRAP toward membrane fraction in adipocytes [108]. In vWAT, PAI-1 level, markers of inflammation and adipocyte hypertrophy, was downregulated in obese rats after IRAP inhibition [109] (Fig. 25.4). Other study on IRAP-knockout mice fed a high-fat diet showed protective effect of

4. Additional angiotensins

aminopeptidase deficiency against the development of obesity, through the suppression of PAI-1 expression in adipocytes development, upregulation of UCP-1mediated thermogenesis in brown adipose tissue, and increased energy expenditure [110] and attenuated PAI-1 expression in differentiated preadipocytes isolated from sWAT [111]. Consequently, intervention of IRAP/AT4R may be a potential strategy against obesity [112].

4.3 Alamandine Recently, a new biologically active angiotensin, alamandine, was discovered. Alamandine is formed either through cleavage of Ang II to Ang A with subsequent hydrolysis of Ang A via ACE2 or via decarboxylation of Ang (1e7) [95]. Functional studies in blood vessels and transfected cells have provided evidence that the receptor for alamandine is the MrgD. However, despite solid functional evidence that the effects of alamandine can be at least partially mediated through binding to MrgD, there is no direct radioligand binding data or other classical pharmacological data to fully demonstrate that MrgD has this function [113]. Alamandine acts at MrgD receptors to elicit similar cardiovascular actions as Ang (1e7), producing vasodilatory and cardioprotective effects, mainly by oxidative stress suppression [113,114]. Furthermore, an earlier study showed that alamandine prevented doxorubicininduced nephrotoxicity induced in rats [115]. Little is known about the function and mechanism of the alamandine in modulating WAT. However, the Mas and MrgD receptors have opposing actions in this tissue, which the alamandine could be modified, degraded, or binds to other receptors in adipocytes. Alamandine can reduce the expression and secretion of leptin through activation of cytotoxic signal transduction and enhanced inducible nitric oxide synthase (iNOS) expression and the coagulation system by PAI-1 induction in vWAT [116] (Fig. 25.4). Also, alamandine levels have not been determined in humans; however, the Ang (1e7) predominates relative to alamandine under normal conditions and, in chronic kidney disease, blood levels of alamandine rise [117]. There are currently no more studies exploring the role of alamandine in lipid metabolism, energy balance, or (patho)physiology of adipose tissue. In fact, it is well known that adipocytes express all components of the RAS, including aminopeptidases (A and N), leading to the local production of Ang III and Ang IV (respectively) and alamandine [99]. In addition, low levels of Ang V were identified in adipose tissue, but it could not be quantified in a reproducible way. This peptide, Ang V, was shown to be derived from Ang (1e7) at a low concentration and is known to have AT4R agonistic effects [23]. Given its recent discovery, an opportunity exists for research exploring the effects of angiotensin degradation products on metabolic function and related differences in white (visceral and subcutaneous), brown, and beige adipose tissue.

4.4 Final remarks More than 30 years ago, the scientific community was convinced that Ang II, the unique and main effector peptide of the RAS, used only one single receptor to exert

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CHAPTER 25 Angiotensins in obesity: focus on white adipose tissue

its various actions specifically in the cardiovascular system. Even today, the importance of local generation and action of the RAS in different organs, some of them still controversial, its numerous intracellular signaling pathways, its interaction with other membrane receptors, its (patho)physiological functions, and therapeutic targets in the context of the RAS are far from being fully elucidated [118]. Local RAS in adipose tissue is somewhat physiologically and functionally independent of the systemic RAS, although it may actually contribute to the production of circulating angiotensin peptides. These findings highlight the relevance of this system in metabolic regulation, especially in the context of obesity. Ang II is knowingly an important mediator of obesity-induced metabolic alterations, and counterbalancing these effects is recognized as a relevant therapeutic target. ACE inhibitors and Ang receptor blockers are widely used pharmacological tools in obesity and related comorbidities management, although the discovery of its actions locally in WAT is quite new. WAT functions of other angiotensin peptides are even more recent. Ang (1e7) signaling pathway has promising results as potential therapeutic targets, although results are still debatable. Nevertheless, regulation of adipose RAS in (patho)physiological conditions has not been completely elucidated to its full extent. In particular, the novel peptides and receptors that are now known to be part of RAS remain a challenge, partly because its biological effects have not been entirely explored. Questions regarding subcutaneous versus visceral adipose tissue location differences gain prominence given the differential function and regulation between then. In conclusion, although knowledge is still limited on WAT RAS regulation in obesity, interventions involving angiotensins modulation have clear therapeutic potential for tackling obesity and its comorbidities.

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CHAPTER

Angiotensin in the gut: roles in inflammatory bowel disease

26 Yan Chun Li

Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, United States

1. Introduction Angiotensin is the product of the renineangiotensin system (RAS). The classic RAS is a systemic endocrine cascade that plays central roles in the renal and cardiovascular systems for the control of blood pressure and fluid and salt homeostasis. In the past decades, the RAS has evolved and become a more complex system in that the proteolytic cascades and components of the system have been greatly expanded, and local RAS is identified in a variety of tissues and organs, such as the brain, heart, kidney, liver, pancreas, intestine, adipose tissue, and reproductive organs. Local RAS usually has tissue-specific functions that can act in paracrine and autocrine fashions mostly independent of the systemic RAS. Moreover, physiological and pathophysiological activities other than the classic regulation of vasculature tone and intravascular volume have been attributed to the system, such as regulation of inflammation, fibrosis, proliferation, and oxidation. Given the favorable long-term safety profiles of a large number of widely available anti-RAS drugs, it is possible to pharmacologically target the local RAS for disease treatment. In this chapter, we review the RAS in the intestinal tract with a focus on its roles in mucosal inflammation and inflammatory bowel disease (IBD).

2. The renineangiotensin system The RAS is a multicomponent cascade with angiotensin (Ang) II as the predominant effector. The initial substrate of this cascade is angiotensinogen, which is mainly produced by the liver. Angiotensinogen is released into the circulation where it is cleaved by renin to Ang I, a peptide composed of amino acids 1e10. Renin is an aspartic protease mainly produced and released by the juxtaglomerular cells in the kidney [1]. Ang I is further cleaved to Ang II, composed of amino acids 1e8, by angiotensin-converting enzyme (ACE), which is highly expressed in the vascular endothelial cells, especially on the pulmonary vasculature. Ang II is the active peptide that functions through binding to the angiotensin receptors type 1 and 2 (AT1R Angiotensin. https://doi.org/10.1016/B978-0-323-99618-1.00028-3 Copyright © 2023 Elsevier Inc. All rights reserved.

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and AT2R), which are G proteinecoupled seven transmembrane receptors. The dominant physiological effects of Ang II are mediated by AT1R, which include inducing vasoconstriction to increase blood pressure and release of aldosterone and antidiuretic hormone (ADH) for extracellular volume retention [2,3]. AT1R also mediates the activities of Ang II to promote inflammation, fibrosis, cell proliferation, and oxidation [4]. On the other hand, AT2R mediates activities that oppose AT1R, including vasodilation and repression of inflammation, fibrosis, and proliferation (Fig. 26.1). These opposing effects of Ang II mediated by AT1R and AT2R are important to maintain a homeostasis. In this cascade, renin is the rate-limiting enzyme that ultimately determines the production of Ang II. As such, renin synthesis and release are stimulated by abnormal physiological conditions such as volume depletion, decreased renal perfusion pressure, and sympathetic activation [1]. Given the importance of the RAS in the renal and cardiovascular systems, pharmacological drugs that target this cascade, including renin inhibitors, ACE inhibitors (ACEIs), and AT1R blockers (ARBs), are widely prescribed for blood pressure control and renal disease treatment [5]. Most of these drugs on the market have relatively well-tolerated long-term safety profiles. Research in the past decades has resulted in the expansion of the RAS. Renin is processed from prorenin, an inactive precursor that contains a 43-amino acid

FIGURE 26.1 The expanded RAS cascade and its biological effects. ACE, angiotensin-converting enzyme; ADH, antidiuretic hormone; Ang, angiotensin; APA, aminopeptidase A; APN, aminopeptidase N: AT1R, angiotensin receptor type 1; AT2R, angiotensin receptor type 2; AT4R, angiotensin receptor type4; MasR, Mas receptor. The nonclassic components of the RAS are marked in blue.

3. Local renineangiotensin system in the intestine

N-terminal prosegment sequence to block the active substrate pocket. Prorenin activation has proteolytic and nonproteolytic mechanisms. Proteolytic activation involves the removal of this propeptide sequence, and nonproteolytic activation involves conformational unfolding of the propeptide that exposes the enzymatic cleft [6]. Prorenin and renin can function like a ligand to bind to a membrane receptor termed (pro)renin receptor (PRR, ATP6AP2) [7]. Prorenin binding to the PRR induces conformational changes that leads to its nonproteolytic activation to cleave the angiotensinogen substrate [8]. Moreover, binding of PRR by prorenin or renin triggers intracellular extracellular signalerelated protein kinase (ERK) 1 and ERK2 signaling that promotes fibrosis and inflammation [7e9] (Fig. 26.1). ACE2, a homolog of ACE, is well known to function as a viral receptor to mediate SARS-CoV-2 coronavirus entry into the host cells that cause the COVID-19 pandemic [10,11], but as an enzyme, ACE2 cleaves Ang I to Ang 1e9 and Ang II to Ang 1e7 [12,13], and Ang 1e7 binds to Mas membrane receptor to trigger effects that oppose AT1R including vasodilation, fluid excretion, and suppression of inflammation and fibrosis (Fig. 26.1). Finally, Ang II can be further cleaved to Ang III and Ang IV by aminopeptidase A (APA) and aminopeptidase N (APN), respectively [14,15], and Ang IV activates AT4R to exert counteracting AT1R effects (Fig. 26.1).

3. Local renineangiotensin system in the intestine In addition to the systemic RAS that works in an endocrine fashion, local RAS exists in many tissues/organs that may act by paracrine and/or autocrine mechanisms [3]. Here, we only discuss the local RAS in the intestine. All components of the RAS have been found in the intestine of rodents and humans, namely in the epithelial, stromal, muscular, and immune compartments [16e18]. Renin, angiotensinogen, ACE, AT1R, and AT2R, as well as Ang II, Ang [1e7], ACE2, and Mas receptor, were detected in normal human colons and terminal ileums by RT-PCR and immunostaining, predominantly in the epithelium and lamina propria, with AT1R located in the epithelial cells, myofibroblasts, macrophages, and vascular walls and AT2R in mesenchymal cells [19,20]. These studies also identified renin and ACE in epithelial and mesenchymal cells and vascular walls, and higher ACE2 in the ileum than in the colon [19,20]. The expression of renin, angiotensinogen, ACE, AT1R, and AT2R was also detected in rat small intestinal enterocytes, and immunostaining revealed robust expression of AT1R and angiotensinogen at the brush border membrane [21]. Similarly, the RAS components are also expressed in mouse intestine, and genetic deletion of serineethreonine kinase Lkb1 from mouse intestinal epithelial cells led to marked induction of renin and ACE and local production of Ang II in the gut [22]. This work revealed a critical role of Lkb1 in the regulation of the intestinal RAS. Moreover, PRR is expressed in the intestine, and depletion of PRR from gut mucosal epithelial cells led to colon disorganization and development of microadenoma [23]. Elevation of colonic ACE2 expression is correlated with inflammation in IBD, which may increase the susceptibility of SARS-CoV-2 infection in patients with IBD [24,25].

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The physiological roles of the intestinal RAS have been studied in the past decades. The functions of the intestinal RAS reported in the literature include regulation of mucosal salt and fluid transport, glucose transport, intestinal muscle contraction, and gut motility. Fluid and salt absorption is a major function of the intestine. Early studies reported that exogenous Ang II was able to stimulate ion and water absorption in the small intestine by a dose-dependent fashion [26]. Consistent with this finding, Ang II directly stimulates the expression of gut epithelial sodiume hydrogen exchanger (NHE)-3 in colonic epithelial cells [27]. NHE3 is a major absorptive sodium transporter in the intestine [28]. Transient sodium load can induce the intestinal RAS and enhance this sodium transporter expression in the small intestine of salt-sensitive rats [29], confirming a critical role of the intestinal RAS in sodium homeostasis. Ang II was also reported to stimulate SGLT1-dependent glucose uptake in rat small intestine [21]. Ang II can elicit dose-dependent contractions of the longitudinal muscle of small intestines from rats and humans, which is mediated by AT1R [30e32]. Overactivation of the local RAS in the intestine due to Lkb1 depletion induced cell proliferation and intestinal tumorigenesis [22]. Studies also suggest that Ang II is involved in intestinal cholesterol absorption in humans through upregulating the expression of NPC1L1, a key molecule in intestinal cholesterol absorption [33]. Moreover, as discussed in the following, overactivation of the local RAS in the gut can stimulate intestinal inflammation leading to colitis.

4. The renineangiotensin system and inflammatory bowel disease Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a major disorder in the gastrointestinal tract in humans [34]. Colitis in UC patients is limited in the colon, whereas inflammation may occur throughout the entire gastrointestinal tract in CD patients. The etiology of IBD is complex and not completely understood at present, but it is generally believed that both genetic and environment factors contribute to the development of IBD; ultimately, inappropriate activation of the intestinal mucosal immune system, particularly the adaptive immune system, is the key driver of colitis [35,36]. For example, CD4þ T helper (TH) cell lineages, including TH1, TH2, and TH17 cells, are known to play important roles in driving mucosal inflammation, as proinflammatory cytokines produced by these cells are critically involved in the initiation and progression of colitis. There are different pathological causes that can lead to overactivation of the local immune system in the gut. For example, dysfunction of gut mucosal epithelial barrier is a common cause of inflammation in IBD, as luminal microbiota invasion can trigger inflammatory reaction of the mucosal immune system [37,38]. In the past decades, emerging experimental and clinical evidence suggests that activation of the RAS in the gut promotes local inflammation and thus may be involved in the pathogenesis of colitis; as such, targeting the RAS might be a new therapeutic strategy for the management of IBD. In the following, we review the preclinical (animal) and clinical (human) evidence in the regard.

4. The renineangiotensin system and inflammatory bowel disease

A body of literature from animal studies has demonstrated critical roles of the RAS in the development of colitis. Chemically induced murine colitis models are the most commonly used experimental models in IBD research, which include models induced by dextran sodium sulfate (DSS), 2,4,6-trinitrobenzene sulfonic acid (TNBS), and oxazolone [39]. In TNBS model, genetic deletion of the angiotensinogen (Agt) gene in mice resulted in marked attenuation of colonic inflammation [40]. Based on this finding, this work confirmed that subcutaneous infusion of losartan (an ARB) suppressed colitis and reduced the production of proinflammatory cytokines in the colon. Similarly, in DSS model, mice carrying genetic deletion of the AT1Ra (Agtr1a) gene developed less severe colitis with lower production of proinflammatory cytokines in the colon relative to wild-type mice [41,42], and treatment with candesartan (an ARB) could suppress colitis in DSS-induced mice [42]. On the other hand, our studies demonstrated that transgenic mice that overexpress renin developed much more severe colitis compared with nontransgenic mice in TNBS model, leading to a high rate of mortality (>50%), but the severe colitis in these transgenic mice was ameliorated by treatment with a renin inhibitor (aliskiren) [43]. Importantly, this high renin-induced colonic inflammation is independent of high renin-induced hypertension. We further showed that chronic infusion of Ang II into nontransgenic mice exacerbated colitis, mimicking the transgenic mice, and blockade of the AT1R with losartan treatment was able to attenuate colitis [43]. Consistent with its colitis-promoting role, components of the RAS, including renin, angiotensinogen, ACE, AT1R, and mucosal Ang II, are highly induced in the colon of experimental colitis models [44,45]. The RAS is known to promote TH1/TH17-mediated autoimmunity [46]. In fact, one important mechanism for the RAS to promote colitis is through induction of mucosal TH1 and TH17 immune responses [44]. Mucosal TH1 and TH17 activation is critically involved in colitis progression [36]. We found that in TNBS model the renin transgenic mice, which constitutively produce a high level of Ang II, displayed more robust TH1 and TH17 immune responses compared with the wild-type mice due to overactivation of the JAK2/STAT pathway, and tofacitinib, a pan-JAK inhibitor approved for the treatment of rheumatoid arthritis and ulcerative colitis [47,48], was able to suppress colonic inflammation in this colitis model [44]. T lymphocytes express a high level of AT1R [46], and our work confirmed that Ang II can promote TH17 cell differentiation via the JAK2/STAT pathway [44]. Ang II activates JAK2 by inducing Src-homology phosphatase 2-mediated AT1R-JAK2 interaction [49,50], or by the PI3eCaþþ and diacylglycerol-protein kinase C axes in a G proteinedependent fashion [51]. As the AT1R-JAK/STAT pathway also exists in gut epithelial cells, Ang II can target the mucosal epithelial cells to disrupt the mucosal barrier integrity, thus promoting mucosal inflammation. Indeed, RAS activation or Ang II infusion can induce colonic epithelial cell apoptosis by activating the proapoptotic pathway, including PUMA upregulation and caspase 3 cleavage, leading to increased mucosal barrier permeability [43,52,53]. We further demonstrated that Ang II also directly upregulates myosin light chain (MLC) kinase and MLC phosphorylation in intestinal

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epithelial cells via the JAK2/STAT pathway, leading to epithelial tight junction dysfunction [44,54,55]. Therefore, Ang II can act on both the immune and epithelial compartments to drive gut mucosal inflammation. Clinical data accumulated over the past decades support the involvement of the RAS in the pathogenesis of IBD in human patients. We observed a dramatic upregulation of renin in the inflamed lesions from patients with UC or CD, and this renin induction appeared to be widespread in the inflamed region, occurring in both the epithelial and stromal/immune components of the mucosa [44]. This observation suggests that mucosal renin upregulation may be a major cause for local RAS activation and increased mucosal Ang II production in IBD. High circulating renin was also observed in patients with IBD [20]. Consistently, several studies reported elevation of colonic mucosal Ang II levels in both CD and UC patients [56,57]. It appears that inflammation is a common factor driving renin expression in UC and CD, and renin induction in turn drives inflammation via the Ang II-JAK2/STAT signaling, forming a vicious circle in the colonic mucosa to promote colitis progression. Proinflammatory cytokines such as TNF-a and IL-1 can stimulate renin release from the kidney [58], but how colonic inflammation drives mucosal renin expression is unclear. Recent studies suggest that imbalance of the RAS may contribute to intestinal inflammation and fibrosis in IBD [20]. This work reported that Ang (1e7) suppressed and Ang II stimulated human colonic myofibroblast proliferation. Patients with IBD had higher ACE2/ACE ratio than controls without IBD. Colonic fibrosis was positively correlated with Ang II level and inversely with ACE2 activity. Elevation in circulating ACE2 and Ang (1e7) levels was also reported in another IBD patient cohort [59]. The role of nonclassic RAS components in IBD requires more investigations. Given the potential role of the RAS in the pathogenesis of IBD, the most important question is whether anti-RAS drugs have therapeutic values in the treatment of IBD. A body of circumstantial evidence, both preclinical and clinical, appears to lend support to this question. A large number of preclinical studies have demonstrated impressive therapeutic activities of renin inhibitors, ACE inhibitors, and ARBs to suppress colonic inflammation and ameliorate colonic damage in various experimental colitis models [42,43,60e63]. Moreover, improved clinical outcomes have been reported in patients with IBD who are on anti-RAS drugs. In a study that involved a cohort of 130 IBD patients, the patients with ACEI/ARB exposure were found to have fewer hospitalizations, operations, and corticosteroid use compared with matched controls [64]. In another study with 296 patients with IBD (207 CD and 89 UC), the patients who required surgery and hospitalization over two years were found less often treated with ACE inhibitors and ARBs than the patients not requiring surgery or hospitalization [20]. Another study reported that, of 150 CD patients with hypertension, the use of ARBs was significantly associated with milder IBD course and lower rates of immunomodulator use, suggesting a possible protective effect on overall IBD outcome by targeting the RAS [65]. Together, these promising retrospective observational data warrant future randomized clinical trials to assess the therapeutic efficacy of anti-RAS drugs in IBD.

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5. Perspectives Emerging experimental and clinical evidence indicates that the local RAS and angiotensin II in the gut play multiple pathophysiological roles, and the potential involvement of the RAS in the pathogenesis of IBD is a particularly interesting subject. With the increasing prevalence of IBD around the world and limited therapeutic tools to treat this disorder, anti-RAS drugs as new therapeutic options for IBD management are worth more exploration. Different classes of anti-RAS drugs may have different therapeutic efficacies against colitis. Randomized clinical studies are particularly needed to ascertain the therapeutic values of targeting the RAS for the treatment of IBD. Generally speaking, as the gastrointestinal tract is not considered as a classic RAS target, our insights into the relationship between the RAS and gastrointestinal physiology and disease remain limited. As such, more investigations into this area are needed.

Acknowledgments Work in the author’s laboratory at the University of Chicago is supported by funding from the National Institutes of Health. The author declares no conflicts of interest.

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The renineangiotensin system in gastrointestinal functions

27

Maria Grazia Zizzo1,2, Rosa Serio1 1

Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy; 2ATeN (Advanced Technologies Network) Center, University of Palermo, Palermo, Italy

1. Introduction Renineangiotensin system (RAS) is classically recognized as an endocrine system, playing a pivotal role as a regulator of cardiovascular and renal functions. However, accumulating data have progressively demonstrated the presence of a local RAS in many tissues such as the brain, heart, kidney, adipose tissue, skeletal muscles, glands, and last but not least, the gut. The introduction of the concept of “local” or “tissue” RAS in the gut, involved in tissue homeostasis with paracrine/autocrine functions, has gradually evolved over the past years, supported by two major technical advances, namely, the use of molecular biology and the availability of knockout murine models with altered expression of RAS components [1]. Although the identification of expression and function of the RAS components throughout the gastrointestinal tract in animal models and humans has been investigated only recently, various data confirmed the presence of the genes for all RAS components including renin, angiotensinogen, angiotensin-converting enzyme (ACE), and angiotensin II receptor type 1 and type 2 (AT1 and AT2), confirming the idea of potential physiological actions of angiotensin II. ACE and renin immunoreactivity are detectable in blood vessels (in particular microvascular endothelium) in mesenchymal cells [2] and in the small intestinal mucosa [3] with a particular representation in microvilli and brush borders where mucosal ACE may function as a brush-border membrane peptidase [4] indicating the enteric source of angiotensin II [5]. Angiotensin-converting enzyme 2 (ACE2), a homolog of the classic enzyme ACE, and an important negative regulator of the classical RAS, is also highly expressed in the gut. ACE2 is able to process angiotensin II to form the heptapeptide angiotensin (1e7) that in turn binds to the membrane receptor Mas. ACE2 in the gut counteracts the ACE/angiotensin II/AT1 receptor axis but, intriguingly, can have RAS-independent functions. ACE2 has been shown to play a critical role in the regulation of intestinal innate immunity, amino acid homeostasis. In this regard, as will Angiotensin. https://doi.org/10.1016/B978-0-323-99618-1.00001-5 Copyright © 2023 Elsevier Inc. All rights reserved.

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be further described, an essential role of ACE2 for the expression of certain amino acid transporters in the small intestine has been recently described. Additionally, Ace2 expression seems to regulate gut microbiome diversity and composition in mice, as well as the microbiome can alter colonic Ace2 expression [6]. The short angiotensin peptides, angiotensin III, and angiotensin IV, are also found in the gut and, through activation of specific receptors, can elicit own physiological responses. In particular, angiotensin IV acts through AT4 receptors, also called insulin-regulated aminopeptidase (IRAP) due to a role in insulin-regulated glucose uptake. The angiotensin IV/IRAP axis is expressed and functional in the human esophageal mucosa affecting glucose uptake [7]. So far, very little research has been devoted to the effective role and functional significance of RAS in the gut even if the gastrointestinal tract is responsible for control of liquid, nutrients, minerals, and vitamins, but also of their digestion, absorption, and excretion, controlling fluids and electrolytes homeostasis. In this chapter, we will review the actual knowledge of physiology/pathophysiology of local RAS in the gut as paracrine regulator of the gastrointestinal muscular wall contractility and epithelial functions. The emerging bidirectional interaction between the microbiome and RAS responsible for intestinal homeostasis is out of the scope of this chapter, and it can been found elsewhere [8].

2. RAS and gut motility The gastrointestinal tract is as a two-layered muscular tube with an inner mucosal layer. This system appropriately mixes and propels its contents from oral to anal, allowing digestion and absorption of the nutrients. Peristalsis and segmentation, the main patterns of intestinal motility, are the result of interplay among smooth muscle cells, interstitial cells of Cajal (ICCs), and the enteric neural circuits (the enteric nervous system). In addition, motility can be influenced also by hormonal/ paracrine/autocrine factors. The spasmogenic action of angiotensin II on vascular smooth muscle is well documented, but its actions on the gastrointestinal smooth muscle still deserves more attention. First evidence of angiotensin II contractile effects on gut came in the early 1960s from the pioneer studies [9,10] showing that the peptide produced contraction of rabbit and guinea pig ileum via stimulation of the nervous system.. Since then, growing evidence confirmed the contractile action of this peptide and demonstrated that it is mediated by specific receptors, member of a superfamily of seven membrane-spanning regions linked to G proteins, classified as AT1 and AT2 receptors. A majority of angiotensin II actions seems to be related to AT1 receptor activation. AT2 receptors are initially recognized as playing an important role during fetal development; growing evidence suggests that they are able to contrast AT1 receptoremediated responses also in adults.

2. RAS and gut motility

The contractile response of angiotensin II can be due to activation of AT1 receptors located directly on the smooth muscle cells, involving activation of phospholipase C, hydrolysis of phosphatidyl inositol 4,5-bisphosphate, production of diacylglycerol and inositol 1,4,5-trisphosphate (IP3), and increase in the levels of intracellular calcium, essential step for muscular contraction. AT1 receptors can also lead to activation of tyrosine kinase pathway or to influx of calcium from extracellular space [11]. In addition, angiotensin II can cause muscular contraction via an indirect mechanism due to activation of AT1 receptors located on neural or mesenchymal cells [5] leading to the release of excitatory mediators, such as acetylcholine (ACh) or substance P, autacoids such as histamines or prostaglandins. Conversely, activation of AT2 receptors in mammals induces relaxation due to inhibitory effects on voltage-dependent calcium channels resulting in a reduction of neurotransmitter release, as ACh, from enteric neurons or to activation of intracellular factors, which modulate the cyclic guanosine monophosphate (cGMP)/nitric oxide (NO) pathway [12].

2.1 Upper gastrointestinal tract: esophagus, lower esophageal sphincter, and stomach Early studies demonstrated that angiotensin II caused contraction of the lower esophageal sphincter (LES) smooth muscle in opossum and rabbit, predominantly via activation of AT1 receptors on the smooth muscle cells, in turn involving multiple intracellular pathways [13]. Subsequently, the contribution of RAS to the modulation of motor activity of human esophagus was described in an elegant study by Casselbrant [14], suggesting the existence of a local RAS in the wall musculature of the distal human esophageal body and lower esophageal sphincter. This study indicated a pronounced local expression of most RAS components, including the AT1 and AT2 receptors, in human esophagus, and studied the functionality of these receptors using an in vitro pharmacological approach. Angiotensin II was able to stimulate the human distal esophageal musculature in vitro, via activation of the AT1 receptor subtype, as demonstrated by the antagonistic effect exerted by losartan, AT1-receptor antagonist, but not by the AT2-receptor antagonist PD123319. Moreover, immunoreactivity to AT1 receptors was detected in the musculature, and angiotensin II effect was insensitive to the neural blocker, tetrodotoxin (TTX), indicating a direct action on smooth muscle (Fig. 27.1). In the same study [14], esophageal evoked contractions were recorded in vivo in healthy volunteers in the presence and absence of a selective AT1 receptor antagonist, candesartan, demonstrating that angiotensin II plays a role in the physiological control of the human esophagus. Further study from the same group showed changes in the enzymes responsible for angiotensin II production and a shift in receptor expression from AT1 receptors to Mas receptors in patients with achalasia [15]. However, it remains unknown whether or not components of the RAS might play a significant role in the pathophysiology of achalasia or of other esophageal dysmotility disorders.

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FIGURE 27.1 Schematic representation of the RAS effects on motor function in esophagus (left) and stomachs (right). Excitatory effects mediated by postjunctional AT1 receptors in esopha gus and at pre- and postjunctional AT1 receptors in stomach. ENS, enteric neuron; NT neurotransmitter.

So far, there is little information available about the regulation of angiotensin II on gastric motility and its cellular mechanism, although both AT1 receptors and AT2 receptors were detected in gastric smooth muscle cells [16] and angiotensinogen and angiotensin-generating enzymes; in addition, AT1 receptors and AT2 receptors were detected in gastric mucosa [17]. Early in vivo studies demonstrated in rat a delay in gastric emptying in the response to angiotensin II [18]. The few in vitro studies of angiotensin II effects on gastric tissue indicated its ability to induce excitatory effects. In human stomach, angiotensin II induces contractile effects [19] via both direct and neurally mediated mechanisms [19] (Fig. 27.1). Subsequently data from animal preparations described angiotensin II contractile effects on gastric smooth muscle in specimens from the guinea-pig, squirrel, and rat [20e22]. Indeed, in guinea pig stomach, angiotensin II, via AT1 receptors, promotes gastric motility without any involvement of enteric nerves [21] inducing extracellular calcium influx and by Ca2þ release from both ryanodine and inositol-1,4,5trisphosphate (IP3)-sensitive calcium stores on the muscle cells. To date, there is no evidence about an AT2 receptor involvement in gastric motility, in vivo or in vitro.

2.2 Small intestine Local RAS participates in the regulation of many activities of small intestine, influencing motility, secretory-transport processes, adsorption, and protective reactions. The majority of the informations available on RAS and small intestine concerns the

2. RAS and gut motility

modulation of mucosal function, although as mentioned before, in the first years of 1960s, pioneer studies suggested a spasmogenic action of angiotensin II in small intestinal preparations [9,10]. In 1968, Beleslin [23] showed that angiotensin II was able to contract guinea pig ileum, but it influenced peristaltic reflex only at high concentrations. However, when the peristaltic reflex was blocked by ganglion blocking agents, it was restored by angiotensin II. Thus, they postulated an action of angiotensin II on postganglionic nerve endings, on ganglion cells, and on smooth muscle. Duggan [24] et al. studied the distribution of angiotensin II receptors in rats describing high expression in the ileum followed by duodenum and jejunum. Angiotensin II-binding sites are mainly detected in each intestinal segment of the intestine in the muscle layers, with a more prevalent expression of AT1 receptors compared with AT2 receptors. Moreover, ACE was distributed in both the mucosa and the muscle layers. These observations allowed the authors to conclude that locally generated angiotensin II played a role in the control of intestinal functions. Subsequently, other authors addressed the pharmacological characterization of the angiotensin II-induced contractions in isolated rat small intestinal muscle preparations [25,26]. In particular, Ewert and colleagues reported that exogenous angiotensin II induced contractile effects in all parts of the rat small intestine. Interestingly, the amplitudes of these contractions showed a striking regional dependence; duodenal muscular preparations were less responsive to angiotensin II stimulation, whereas ileal muscular strips exhibited the maximal responsiveness. The ileal responses as suggested by pharmacological evidence, as well as by receptor protein analyses, resulted to be mediated via AT1 receptors, whereas no AT2 receptor effects were detected. The authors did not investigate if the induced contraction was mediated by direct action on the muscle or by an indirect action via enteric nerves, although they observed that angiotensin II-induced contractions of rat ileum were influenced neither by the adrenolytic guanethidine nor by the muscarinic cholinergic antagonist atropine [25]. Ongoing studies in our lab indicate that angiotensin II contracts jejunum smooth muscle through activation of postjunctional AT1 receptors, involving Ca2þ mobilization from intracellular stores and Ca2þ influx from extracellular space. Concurrently, we are highlighting a role of AT2 receptors, which when activated would counteract the excitatory effects mediated by AT1 receptor, via enteric nerves and increase in NO production [27] (Fig. 27.2). Ludtke [19] et al. demonstrated that angiotensin II dose-dependently contracts human duodenal smooth muscle preparations. Indeed, angiotensin II-induced contractions in human small intestine were mediated by AT1 receptors, since the AT1 receptor antagonist losartan inhibited them, while the AT2 receptor antagonist PD123319 had no effect. This conclusion was supported also by the predominance of AT1 receptor compared with AT2 receptor protein expression in the wall musculature [25]. Expression of other components of RAS, i.e., angiotensinogen and ACE was detected in human jejunal muscle wall [28]. Interestingly, both AT1 and AT2 receptors were found also in the myenteric plexus [25]. In conclusion, the physiological significance of angiotensin II-induced effects on small intestinal musculature both in humans and in animals is not fully elucidated, as well as the possibility

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FIGURE 27.2 Schematic representation of the RAS effects on motor function in small intestine: duoden um (left), jejunum (center), and ileum (right). Excitatory effects mediated by postjunction al AT1 and AT4 receptors and inhibitory effects mediated by prejunctional AT2 receptors. ENS, enteric neuron; NO, nitric oxide.

that pathological conditions may promote AT2 receptor expression as well as increase in local angiotensin II generation leading to major angiotensin IIassociated effects on the intestinal motor activity (Fig. 27.2). Lastly, a study of Malinauskas [7] demonstrated that the enzymes necessary for angiotensin IV biosynthesis are expressed in human jejunal smooth muscle and angiotensin IV contracts both longitudinal and circular muscle layers. However, although IRAP/AT4 receptors were detected both in myenteric plexus and in the muscle cells, pharmacological analyses in vitro suggest that angiotensin IV effects were mainly mediated via postjunctional AT1 receptor activation (Fig. 27.2). Therefore, so far, it is no possible to evaluate any potential physiological and pathophysiological role of local angiotensin IV biosynthesis nor the function of IRAP/AT4 receptors in the contractility of human small intestinal muscular layer. Future investigations are mandatory to clarify this issue.

2.3 Large intestine The presence of mRNA for angiotensinogen, renin, ACE and ACE2, and AT1 and AT2 receptors has been demonstrated also in the colonic wall in both human and animal models indicating that RAS bioactive peptides can be locally generated to control colonic functions [5,29e31]. In particular, by RT-PCR and immunohistochemical analyses, renin, ACE, and AT1 and AT2 receptors have been found in epithelial cells of the colon, as well as in the lamina propria. Renin, AT1 receptors,

2. RAS and gut motility

and ACE2 are also found in colonic microvessels; the presence of both AT1 and AT2 receptors is reported in the crypts; and the AT1 receptor was found in colonic myofibroblasts [29,32]. The presence of both AT1 and AT2 receptors was revealed in smooth muscle cells and on submucosa and myenteric plexus [2]. In the first years of 1970s, contractile effects of angiotensin II in human and rat colonic smooth muscle have been showed [33,34]. Then, in rat colon, involvement of cAMP and calcium influx was suggested [35]. Since then, this topic loose attention in the research community and only recently the action of angiotensin II on rodents and human colon got new attention [25,30,31,36]. As commonly observed in smooth muscle preparations, the contractile actions triggered by angiotensin II in rodents and human colon are mediated by AT1 receptors [31]. In mouse, we found a regional difference in the mechanism of action of angiotensin II since tetrodotoxin, neural blocker, partly reduced the contractile response to angiotensin II in the proximal colon, while abolishing it in the distal colon. Therefore, angiotensin II is able to regulate smooth muscle tone in murine proximal colon acting both directly on smooth muscle cells and indirectly via modulation of neurotransmitter release. Instead, only neural mechanisms are involved in the angiotensin II effects in murine distal colon. The neural mechanisms involves tachykinins and ACh, being ACh the final mediator causing smooth muscle contraction [31] (Fig. 27.3). In human colon, activation of muscular and neural AT1 receptors mediates the angiotensin II-positive modulation of the spontaneous contractile activity. In this

FIGURE 27.3 Schematic representation of the RAS effects on motor function in large intestine: proximal colon (right), distal colon (center), internal anal sphincter (right). Excitatory effects mediated by pre- and postjunctional AT1 receptors and by postjunctional Mas receptors and inhibitory effects mediated by prejunctional AT2 receptors. ENS, enteric neuron; ACh, acetylcholine; TK, tachykinins; NO, nitric oxide.

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case, neural AT1 receptors modulate the release of tachykinins, being neurokinin A the final mediator causing smooth muscle contraction [30]. The pivotal role played by AT1 receptors in mediating contraction has been demonstrated also in rat colon [36,37]. Interestingly, inflammation affects the expression of both angiotensin II receptors, resulting to be upregulated in the colon of a rat model of inflammatory bowel disease (IBD) [36]. The response to angiotensin II was lower in the inflamed tissues. This difference was not only due to the different contractility of inflamed tissues, but also due to an enrollment of inhibitory AT2 receptors, located at prejunctional level and leading to the synthesis of NO, thus counteracting AT1 receptor effects in rats with colitis. In fact, we described that in experimental model, the 2,4dinitrobenzene sulfonic acid (DNBS) rats of colitis, the function of the AT2 receptors was revealed, since the contractions to angiotensin II were increased in the presence of PD123319, AT2R antagonist, in inflamed tissues becoming comparable with the response observed in control tissues. A major finding of our study was the observation that the AT2 receptor antagonist was able per se to improve colonic contractility in inflamed tissues in vitro. Thereafter, we investigated the potential alleviating effects of the in vivo treatment of PD123319 in DNBS rats. Our data demonstrated that AT2 receptor antagonist treatment leaded to a reduction of the inflammatory process and to the recovery of musculature functionality. AT2 receptors, likely via NF-kB pathway and reactive oxygen species generation, would play a key role in the inflammatory events in the course of DNBS-induced experimental colitis [38]. However, further studies are required to elucidate AT2 receptor recruitment, and the mechanisms by such an event may be involved in the progression of intestinal inflammatory disease. Angiotensin II contracts also internal anal sphincter via AT1 receptors [39]. However, inhibitory AT2 receptors have been reported to mediate relaxation of rat internal anal sphincter in response to high concentration of angiotensin II, which induced desensitization of excitatory AT1 receptors. AT2 receptors would mediate inhibitory effects via neuronal NOS/soluble guanylate cyclase pathway [39] (Fig. 27.3). Moreover, De Godoy et al. [39] suggested also a potential role of angiotensin (1e7) and Mas receptors and in the regulation of gastrointestinal smooth muscle motility (Fig. 27.3), showing that angiotensin (1e7) dose-dependently reduced the basal tone of spontaneously contracted internal anal sphincter of rats and the effect was abolished by a specific Mas antagonist, A-779, which did not affect contractile response of angiotensin II. As already indicated, additional studies are necessary to determine the role played by alternative RAS in the physiological regulation of gastrointestinal contractility.

3. RAS and epithelial functions One of the main roles of gut is the digestion of the food and the adsorption of the water and nutrients. Indeed, epithelial cells of the mucosa, with their villi, crypts, and microvilli, solubilize foods ingested and further degrade them enzymatically

3. RAS and epithelial functions

to simple molecules allowing their absorption across the mucosal epithelium. The amount of fluids moving daily in absorption and secretion back and forth over the intestinal epithelium is important for the regulation of the body fluid and electrolyte homeostasis. Increasing evidence highlights a role of RAS in regulating processes as ion and net fluid secretion/absorption, bicarbonate secretion, glucose absorption, and digestion/absorption of peptides. As already reported, expression of all RAS components has been observed in the mucosa of the different tracts of the human and animal gut [17,32,40].

3.1 Upper gastrointestinal tract: esophagus and stomach RAS components are expressed and functional in human esophageal mucosa in the healthy esophageal mucosa as suggested by Casselbrant et al. [40]. Pharmacological investigations demonstrated that both AT receptors can interfere with epithelial functionality with antagonistic effects. Indeed, AT2 receptor stimulation increases epithelial ion transport, whereas the AT1 receptors inhibit ion movement (Fig. 27.4) [40]. There is relatively scarce information about the RAS control of gastric acid secretion. Using AT1 receptor blocker, Chow et al. [41] suggested that in Naþdepleted rats, in which RAS is activated, the decrease in stimulated acid secretion is due to the regulation of mucosal blood flow by angiotensin II acting through AT1 receptors. Moreover, few functional or pathogenic roles have been attributed to the RAS in the stomach (Fig. 27.4). For instance, an increase of AT1 receptor expression was observed in the gastric mucosa of H. pylori-positive subjects correlating positively with neutrophil infiltration [17].

FIGURE 27.4 Schematic representation of the RAS effects on epithelial function in upper gastrointestinal tract: Opposite effects of AT1 and AT2 receptors on ion transport in esophagus (left) and involvement of AT1 receptors in acid secretion in stomach (right).

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Subsequently, it was reported that in rat stomach, wall angiotensin (1e7) was the main product of angiotensin I conversion [42], but the physiological role of prevalence of angiotensin (1e7) in the control of gastric acid secretion is not clarified yet. In human stomach, AT1 receptors were not found on the parietal cells [17]. Therefore, it was suggested that if AT1 receptors may influence the gastric acid secretion in humans, the effects can be just indirectly by a modulation of mucosal blood flow or via an action on antral endocrine cells [17]. Interestingly, in the same study, it was demonstrated that, in vascular endothelial cells of the gastric mucosa, the expression of neprilysin, an enzyme contributing to the formation of bioactive RAS peptides, such as angiotensin (1e7). Once more, further studies are needed to elucidate the involvement and the relative importance of the bioactive RAS peptides in the control of the gastric secretion.

3.2 Small intestine Duodenal mucosal bicarbonate secretion, a mechanism of defense against luminal acid deposited into the duodenum during gastric emptying, is regulated by mucosa-sensing mechanisms as well as by autonomic reflexes that increase or decrease this process in relation to luminal acid exposure. In rat duodenum, angiotensin II prolongs the inhibition of mucosal alkaline secretion during hypovolemia via the sympathetic system [43]. Moreover, infusion of angiotensin II alone had no effect on basal mucosal alkaline secretion, but when infused in the presence of the selective AT1 receptor antagonist, losartan, a marked increase was observed (Fig. 27.5). The increased mucosal alkaline secretion observed on angiotensin II infusion in losartan-treated animals was absent in the presence of the AT2 receptor antagonist, PD-123319, indicating the existence of AT2 receptors with potent

FIGURE 27.5 Schematic representation of the RAS effects on epithelial function in small intestine: Opposite effects of AT1 and AT2 receptors on bicarbonate secretion (left), ion, and fluid absorption (center), and involvement of AT1, AT2, and Mas receptors on glucose absorption (right). SGLUT, sodium-dependent glucose transporter.

3. RAS and epithelial functions

stimulatory effects on duodenal mucosal alkaline secretion and supporting the view of a counterregulatory function of AT2 versus AT1 receptors [44]. The small intestine is engaged also in the nutrient absorption. Early studies by Levens [45,46] showed that angiotensin II, in rat jejunum segments, exerts a dose-dependent dual action in ion and fluid absorption. Low doses of angiotensin II increased the process, activating AT2 receptors leading to stimulation of sympathetic neuron and nitric oxide (NO)/cGMP pathway, partly stimulating noradrenaline release from sympathetic neurons (Fig. 27.5). Indeed, high concentrations of angiotensin II inhibited absorption, and such an effect, unexpectedly, was due to AT1 receptor stimulation, negatively coupled to cAMP and stimulating prostaglandin E2 production [47e49] (Fig. 27.5). There is a substantial body of evidence demonstrating a pivotal role played by NHE3, a major sodium transporter expressed in the apical brush-border membrane of the intestinal epithelium and of the renal proximal tubule, in the homeostasis of sodium balance and blood pressure. Angiotensin II is able to regulate expression of NHE3 through AT1 receptoredependent mechanisms in the kidney and cultured intestinal epithelial cells [50] and in rat intestine [51], suggesting that such a mechanism is involved in the modulation of intestinal sodium and water absorption. Furthermore, the effect of angiotensin-(1e7) on jejunal water absorption in rats was also demonstrated (Fig. 27.5). Infusion of angiotensin-(1e7) significantly increased jejunal water absorption via nitric oxide and cyclooxygenase-dependent mechanisms and involved multiple angiotensin receptors including the classical AT1/2 receptors [52]. Additionally, proteins in ingested food are hydrolyzed to small oligopeptides and amino and are absorbed across the mucosa in small intestine. Analysis of angiotensin-converting enzyme (ACE1 and ACE2) activities along the intestine of the rat and rabbit demonstrated the highest distribution of the enzymes in the small intestinal brush border of enterocytes participating in the digestion and absorption of dietary peptides [3,4]. Most neutral amino acids are transported across the apical brush-border membrane of the small intestine by luminal broad neutral amino acid transporter B0AT1, which is stabilized by ACE2, and defect in ACE2 expression compromises intestinal uptake of amino acids [53]. The absorption of glucose through the intestine involves a transepithelial transport mediated by sodium-dependent glucose transporter, SGLT-1, located on apical brush-border membrane of enterocyte and by glucose transporter GLUT2, located in basolateral membrane of enterocytes. Wong et al. [54] found evidence in rat small intestine for the existence of locally generated angiotensin II from jejunal and ileal enterocytes leading to a rapid inhibition of SGLT1-mediated intestinal glucose uptake [54]. Enterocytes express angiotensinogen, ACE, and AT1 and AT2 receptors. Addition of angiotensin II to the mucosal buffer inhibited in a dose-dependent manner SGLT1-dependent jejunal glucose uptake, and as indicated by the losartan sensitivity, this effect was mediated by AT1 receptors. Casselbrant et al. [55] demonstrated that also in the human jejunal mucosa, angiotensin II affects the

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function of SGLT1. In particular, angiotensin II exerts a dual action as revealed by in vitro pharmacological analysis: AT1 receptor activation inhibits jejunal glucose/sodium absorption, whereas AT2 receptors exert the opposite action. Once more a further demonstration of counteracting action of AT1 receptors and AT2 receptors (Fig. 27.5). Streptozotocin-induced diabetes mellitus in rat promotes intestinal glucose transport likely as consequence of increased brush-border membrane expression of SGLT1 and of GLUT2, additional pathway for glucose transport [56]. Results from Wong et al. [57] revealed a reduction in the brush border of ACE and AT1 receptors expression resulting in a defective inhibition of intestinal glucose uptake (Fig. 27.5). Interestingly, as compensatory mechanism to counterbalance the higher glucose uptake induced by downregulation of the ACE/angiotensin IIeAT1 receptor axis in diabetes, there was observed an upregulation of ACE2/angiotensin (1e7)eMas receptor axis, which can inhibit glucose uptake and significantly improve oral glucose tolerance [58]. Being aware that development of new drugs targeting ACE2 activity is actually a strategy for new treatment options for diabetic nephropathy [59], data on intestinal transport of glucose indicate that ACE2e angiotensin (1e7)eMas receptor axis can be considered for overall glycemic regulation in diabetic patients. A positive regulation of the ACE2eMas axis was also observed after probiotic supplementation (as. Bifidobacterium longum) improving glycemic and lipid profiles [60].

3.3 Large intestine Colon plays a role in the absorption of electrolytes to prevent secretory diarrhea and the potential fatal loss of electrolytes. The transport is characterized by a net absorption of NaCl, short-chain fatty acids, and water, and net secretion of mucus, bicarbonate, and KCl. There are limited studies on the control of epithelial function by RAS. Early studies showed that angiotensin II-controlled absorption of sodium and fluid by the colonic mucosa is aldosterone-dependent [61]. However, in a rat model of chronic renal failure, AT1 receptors contribute to the increase of colonic sodium absorption [62]. Hosoda et al. [63] provide evidence for a local regulation of Cl secretion by angiotensin II in guinea pig distal colon. Angiotensin II-evoked Cl secretion was mediated by AT1 receptors and involved neural mechanisms via submucosal cholinergic and tachykinergic neurons and prostanoid synthesis pathways. Angiotensin II acts also as a secretagogue agent stimulating serosa-to-mucosa colonic Kþ transport activating different receptors, depending to the doses [64]. Low concentration of angiotensin II activates only AT2 receptors and involves stimulation of barium-sensitive luminal Kþ transports; instead, high concentrations of angiotensin II were able to induce the activation of both AT1 and AT2 receptors, with the further stimulation of Naþ, Kþ, and 2Cl cotransporters [64] (Fig. 27.6).

4. Summary and conclusions

FIGURE 27.6 Schematic representation of the RAS effects on epithelial function in large intestine: Invo lvement of AT1 and AT2 receptors in colonic Kþ secretion1.

4. Summary and conclusions In the past decade, data are accumulating indicating the involvement of the RAS in physiological modulation of gut functions controlling gastrointestinal liquid and electrolyte homeostasis, and smooth muscle contraction. Throughout the gastrointestinal tract, all the components of the RAS have been identified, including both AT1 and AT2 receptors, which can oppositely regulate gut physiological functions via direct activation of intestinal smooth muscle and epithelial cells or indirect action mediated by enteric neurons. Main evidence highlighted a pivotal role of AT1 receptors as responsible of contractile effects on smooth muscle cells and in the regulation of epithelial functions from the proximal to the terminal part of the gut. However, even AT2 receptors take part in the angiotensin II actions in the gut, but so far, further studies should be addressed to improve knowledge regarding their effective contribution and action mechanism. In addition, recent evidence indicates also an important contribute of alternative RAS as ACE2/angiotensin (1e7)/Mas receptor axis in the gut, which seems to participate, counteracting classical RAS functions, to the modulation of fluid and ion movement across intestinal epithelium as well as in the glucose homeostasis. To date, only a marginal contribute in the modulation of gut motility has been revealed; then, further investigations are needed.

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Interestingly, it has been observed that all the component of classical and alternative RAS can be altered in pathological conditions, suggesting their potential modulatory or inductive actions during gastrointestinal pathological conditions. Indeed, data are emerging suggesting RAS ability to modulate inflammatory processes with potential role in inflammatory bowel diseases [65] such as ulcerative colitis and Crohn’s, as well as in carcinogenesis [66]. Encouraging data indicate that the manipulation of this system could be of benefit also in a range of GI pathologies, as gut motility disorder or metabolic disturbances and alterations due to inflammatory conditions. Although clinical data addressing the enteric RAS system are still scarce, results from animal models and preclinical studies provide support for further investigation to target RAS in gastrointestinal disorders.

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CHAPTER

Angiotensin in shock: experimental and clinical studies

28

Emily J. See2, 3, Yugeesh R. Lankadeva1, 3, Rinaldo Bellomo2,3, Clive N. May1, 3 1

Preclinical Critical Care Unit, Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia; 2Intensive Care Unit, Austin Hospital, Melbourne, VIC, Australia; 3Department of Critical Care, University of Melbourne, Melbourne, VIC, Australia

1. Background The renineangiotensin system plays a central role in many homeostatic processes including the control of blood pressure, renal sodium reabsorption, thirst, and the release of aldosterone and vasopressin, as well as influencing fibrosis, inflammation, and angiogenesis. These effects are mediated by the actions of the octapeptide angiotensin II (Ang II) on angiotensin type 1 (AT-1) and type 2 receptors. Since a major effect of Ang II is to increase blood pressure by actions on the AT-1 receptors, the focus of research has been the development of drugs that prevent the synthesis of Ang II or act as antagonists of the AT-1 receptor. Indeed, angiotensin-converting enzyme inhibitors and angiotensin AT-1 antagonists are mainstays in the treatment of hypertension and heart failure. There has been little interest in the use of Ang II in conditions where blood pressure is low, despite it being a vasoconstrictor that is many times more potent than noradrenaline on a molar basis [1]. In 1962 CIBA-Geigy developed HypertensinÒ, a bovine sourced angiotenin II (val5eangiotensin II-asp-b-amide), for the treatment of patients with shock and circulatory collapse. Although HypertensinÒ was used in experimental and clinical studies investigating the physiology of Ang II, it did not gain traction as a treatment and was withdrawn from the market in 2008. More recently, based on findings showing the beneficial effects of Ang II in a clinically relevant ovine model of sepsis [2,3], a synthetic human 5 isoleucineeangiotensin II (GiaprezaÒ) has been developed by La Jolla Pharmaceuticals for the treatment of hypotension in adults with distributive or vasodilatory shock who remain hypotensive despite fluid and vasopressor therapy. In this chapter, we describe preclinical studies demonstrating the cardiovascular effects of Ang II in the healthy state and the effects of Ang II in experimental sepsis and in recent clinical trials.

Angiotensin. https://doi.org/10.1016/B978-0-323-99618-1.00024-6 Copyright © 2023 Elsevier Inc. All rights reserved.

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2. Experimental studies In many species, intravenous administration of Ang II has been demonstrated to rapidly increase arterial pressure by causing peripheral vasoconstriction. The vasoconstrictor effects of Ang II are complex with differential effects on individual organs. In unanesthetized rats, a bolus dose of Ang II that increased mean arterial pressure (MAP) by w50 mmHg caused vasoconstriction and reductions in blood flow in the renal and mesenteric circulations [4]. In contrast, Ang II did not cause vasoconstriction in the hindquarters so that the increased perfusion pressure increased flow. Similarly, in anesthetized cats, a dose of Ang II that increased MAP by 85 mmHg decreased renal flow, but increased femoral flow [1]. In unanesthetized sheep, intravenous infusion of increasing doses of Ang II that increased MAP between 5 and 35 mmHg caused a dose-related vasoconstriction in all the vascular beds monitored [5], although there were marked differences in responsiveness to Ang II in the following order: renal > mesenteric > iliac > coronary (maximum reduction in vascular conductance of 70%, 38%, 24%, and 17%, respectively). These changes resulted in the kidney being the only organ in which Ang II caused a dose-related fall in blood flow. Despite the increase in arterial pressure with Ang II, there was no reflex decrease in heart rate or cardiac output, likely due to the effect of Ang II to desensitize the arterial baroreflex [6,7].

2.1 Sepsis Sepsis is a life-threatening response to infection that can lead to multiorgan dysfunction. It is a major medical problem with a high death rate of 20%e50% and is the leading cause of death in intensive care units (ICU) worldwide [8,9]. It is estimated that globally sepsis accounts for 11 million deaths/year and accounts for almost 20% of world deaths [10]. Sepsis is a frequent cause of admission to intensive care units (ICUs) and accounts for approximately 50% of cases of acute kidney injury (AKI) [11]. Despite decades of research, there are no clinically available treatments to reverse the effects of sepsis and the pathophysiological factors causing septic AKI are unclear. Traditionally septic AKI was proposed to be due to renal ischemia as a result of a decrease in global renal blood flow [12,13]. This hypothesis was based largely on studies in anesthetized rodent models of endotoxemia with a hypodynamic circulation, peripheral vasodilatation, and a decrease in cardiac output, which is different to the more common hyperdynamic circulation with increases in cardiac output seen in human septic patients.

2.2 Ovine model of sepsis We have developed a model of hypotensive, hyperdynamic sepsis induced by intravenous infusion of live Escherichia coli (E. coli) in conscious sheep that closely replicates the changes seen in septic patients. There is a decrease in MAP, accompanied

2. Experimental studies

by increases in heart rate and cardiac output, the development of AKI, respiratory failure, hyperlactatemia, and malaise, and an increase in body temperature [14,15]. During the development of ovine sepsis, there is a high degree of renal vasodilatation that, despite the decrease in MAP, results in an increase in total renal blood flow. Surprisingly, in the face of this renal hyperaemia, AKI occurred, as indicated by an increase in plasma creatinine and decreases in creatinine clearance and urine flow. Similar responses were seen regardless of whether E. coli was given as a single bolus or as a continuous 48-h infusion. We also demonstrated that at 48-h of sepsis there was no renal apoptosis or necrosis [16], which is similar to the situation observed in kidneys obtained at postmortem from septic patients [17,18]. Furthermore, when the E. coli infusion was switched off after 48 h and antibiotics were given, renal function returned to normal in 48 h [19]. Such a rapid recovery could not have occurred if septic AKI was induced by renal cell death as it would take longer than 48 h for renal repair and recovery of function to occur. Together, these findings indicate that a decrease in total renal blood flow resulting in renal ischemia and cell death is not a prerequisite for the development of septic AKI. We have therefore suggested that septic AKI is due to functional changes, not renal cell death. If this is the case, what could be a possible mechanism causing AKI despite renal vasodilatation and a large increase in total renal blood flow, and how could this be treated? We hypothesized that, in sepsis, a greater degree of vasodilatation in the efferent than in the afferent arterioles could account for a decrease in glomerular hydrostatic pressure and glomerular filtration rate (as assessed by creatinine clearance) in the face of an increase in total renal blood flow [20]. There is evidence that Ang II causes a preferential increase in resistance in the efferent compared with afferent arterioles [21], which might be expected to improve glomerular filtration rate in this situation. The use of Ang II in septic patients resistant to catecholamines has been reported in a few case reports [22e24], but it has not been used widely due to concerns about its potent vasoconstrictor actions having deleterious effects on renal blood flow and renal function. It had not, however, been investigated whether these potential adverse effects of Ang II on renal blood flow are functionally important in sepsis. To determine whether preferential efferent arteriolar vasoconstriction is beneficial in this setting, we conducted randomized controlled studies in ovine models of acute and chronic hypotensive, hyperdynamic sepsis and measured the systemic and regional hemodynamic effects and the renal functional effects of Ang II infusion compared with placebo.

2.3 Angiotensin II in early experimental sepsis In conscious sheep previously surgically instrumented with flow probes on the pulmonary, left circumflex coronary, mesenteric, left renal, and left iliac arteries, sepsis was induced by an intravenous bolus of E. coli [3]. By 8e12 h after the bolus of E. coli, animals typically reached the predefined cardiovascular criteria for randomization: 10% decrease in MAP, 50% increase in heart rate, and 30% increase in cardiac output. Data were then recorded for a 120-min pretreatment period before being

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CHAPTER 28 Angiotensin in shock: experimental and clinical studies

randomly assigned to receive a 6-h intravenous infusion of either Ang II (55
78 ng/kg/min, range 4.25e450 ng/kg/min) or vehicle (saline). The dose of Ang II was titrated to maintain MAP at the presepsis control level. Sepsis was associated with peripheral vasodilation, hypotension, tachycardia, and an increase in cardiac output (hyperdynamic sepsis) (Fig. 28.1) [3]. Vasodilatation and increases in blood flow occurred in all vascular beds monitored. In the kidney, renal blood flow increased (292.3
60.5 to 396.6
74.1 mL/min), which was accompanied by oliguria and a 43% decrease in creatinine clearance. Intravenous infusion of Ang II increased MAP to basal preseptic levels, whereas the group treated with vehicle remained hypotensive (Fig. 28.1). Ang II induced a small decrease in cardiac output but did not alter heart rate. Ang II caused constriction in the renal vascular bed and returned renal blood flow to presepsis control levels, but had less potent vasoconstrictor actions on the coronary, mesenteric, and iliac vascular beds. Ang II caused large increases in urine flow and creatinine clearance that were maintained throughout the infusion, whereas in the vehicle-treated group, renal function did not improve. Treatment with Ang II had no effects on arterial blood gases, plasma electrolytes, or acid base variables. 120

Ang II Vehicle

Creatinine Clearance (mL/min)

Mean Arterial Pressure (mmHg)

140 120 100 80 60

I

II

100

*

Ang II Vehicle

III *

80

*

60 40 20

40

I

II

-610 -550 -120 -60

III 0

60

0

120 180 240 300 360

800

600

700

500

Urine Output (mL/h)

Renal Blood Flow (mL/min)

702

400

300

0

I

II

120

240

*

III

*

600

360

*

500 400 300 200

200

100

-720

I

II

-610 -550 -120 -60

III 0

60

120 180 240 300 360

Time (min)

100 0

-720

0

120

Time (min)

240

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FIGURE 28.1 Effects of intravenous angiotensin II or vehicle on mean arterial pressure, renal blood flow, creatinine clearance, and urine flow in unanesthetized sheep. Phase I ¼ control period, 2 h before Escherichia coli administration; Phase II ¼ sepsis control period, 2 h before treatment; Phase III ¼ 6 h of treatment with angiotensin II (Ang II) or vehicle. Data are means
standard deviation, n ¼ 6. *P < .05 comparison between treatment and vehicle.

2. Experimental studies

2.4 Renal bioenergetics Since the effect of Ang II to improve renal function in sepsis may increase renal oxygen consumption and induce bioenergetic failure, we measured global renal ATP during hypotensive sepsis and during Ang II infusion using 31P magnetic resonance spectroscopy. In anesthetized sheep in a 3T MRI scanner with a previously implanted magnetic resonance coil around one kidney, sepsis was induced by a bolus injection of E. coli [25]. In the anesthetized state, after 2 h, MAP had decreased by more than 25 mmHg, there was intense renal vasodilatation with only a minor increase in renal blood flow. At this time, infusion of Ang II restored MAP to control levels, caused renal vasoconstriction, and reduced renal blood flow. At 2 h of sepsis, the renal levels of total ATP, a, b, and g ATP and the total ATP to inorganic phosphate ratio were unchanged from baseline. These levels were also not altered by infusion of Ang II. Thus, in early sepsis, the potent vasoconstrictor Ang II did not reduce global renal ATP levels, indicating a lack of bioenergetic failure. The lack of a decrease in ATP during sepsis and during Ang II infusion suggests the absence of global renal ischemia, but this study does not exclude the possibility that there are heterogenous changes in perfusion in different areas of the kidney during sepsis and also during treatment with vasoconstrictor drugs.

2.5 Intrarenal perfusion and oxygenation in sepsis It is established that the control of intrarenal perfusion and thus oxygen delivery is heterogenous and that the medulla is particularly susceptible to ischemia and hypoxia. Furthermore, it has been proposed that renal tissue ischemia and hypoxia are common pathological features of AKI induced by cardiopulmonary bypass, radiocontrast, and sepsis. However, the measurements of tissue perfusion and oxygenation in such experimental studies were completed in anesthetized animals, and anesthesia has been shown to significantly reduce renal blood flow and renal oxygen delivery. We therefore developed a technique to chronically implant fiber-optic probes in the renal cortex and medulla in sheep allowing continuous monitoring of renal cortical and medullary tissue perfusion and PO2 for at least 2 weeks [26]. Using this technique, we demonstrated that, in unanesthetized healthy sheep, the levels of tissue perfusion and PO2 were similar in the renal cortex and medulla. This is in contrast to the majority of findings in anesthetized animals where tissue PO2 in the medulla is lower than that in the cortex [10,14,15]. We did, however, show that the medulla was more susceptible to ischemia and hypoxia than the cortex during reductions in renal blood flow of 20% and 50% [26]. A similar selective effect on the renal medulla was seen during hypotensive, hypodynamic sepsis in sheep in which renal blood flow and renal oxygen delivery increased. Within 1 h of inducing sepsis, there was a selective decrease in medullary perfusion and PO2, while cortical perfusion and PO2 were maintained [27]. The renal medullary ischemia and hypoxia were maintained for the 24 h of sepsis, and

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CHAPTER 28 Angiotensin in shock: experimental and clinical studies

the levels had not fully normalized 24 h after cessation of the E. coli infusion. It is likely that the sensitivity of the medulla to hypoxia is a result of its meagre blood supply and the large amount of energy required for reabsorption in the proximal tubules and thick ascending limbs of the loop of Henle. The finding that, with the onset of sepsis, medullary ischemia and hypoxia develop rapidly before urine flow and glomerular filtration rate decrease suggests that this phenomenon could contribute to the initiation and progression of septic AKI. It is also likely that the effects of renal hypoxia to reduce renal function in sepsis are enhanced by the high levels of inflammatory cytokines and other oxidative stress mediators.

2.6 Effects of Ang II on intrarenal perfusion and PO2 in established sepsis In view of the finding of renal medullary hypoperfusion and hypoxia in sepsis, it was important to determine the effect of vasoconstrictor drugs on intrarenal perfusion and oxygenation. For these studies, we used an ovine model of sepsis in which E. coli was infused for 32 h and vasopressor drugs or vehicle were given from 24 to 30 h of sepsis at doses titrated to restore arterial pressure to presepsis control levels. Infusion of Ang II (55
78 ng/kg/min) in septic sheep fully restored arterial pressure without reducing heart rate or cardiac output [28] (Fig. 28.2). Ang II induced renal vasoconstriction, reduced renal blood flow and significantly improved renal function as indicated by an increase in urine flow to control levels, a decrease in plasma creatinine and an increase in creatinine clearance. In the septic sheep treated with vehicle, medullary perfusion and PO2 were decreased throughout the 32 h of sepsis (Fig. 28.3). These changes were not altered by infusion of Ang II despite its action to decrease in renal blood flow and renal oxygen delivery. In these studies, we also measured bladder urinary PO2, which changed in parallel with medullary PO2, indicating that this measurement could be used as a noninvasive biomarker of renal medullary hypoxia. Although there is some concern that the inflammatory effect of Ang II may enhance the cytokine storm in sepsis, we found that Ang II had no effect on the increased levels of interleukin 6 or 10 in ovine sepsis [28]. Using a similar protocol, septic sheep were treated with a clinically relevant dose of noradrenaline (0.4e0.8 mg/kg/min), which is the first-choice vasopressor drug used to restore arterial pressure and renal function in septic patients. Noradrenaline restored MAP but did not significantly reduce renal blood flow or renal oxygen delivery [2]. Noradrenaline caused a transient improvement in renal function that was similar to that seen with Ang II (Fig. 28.2). In contrast to treatment with Ang II, however, infusion of noradrenaline at 24 h of sepsis worsened the degree of renal medullary ischemia and hypoxia, with medullary PO2 decreasing from w40 mmHg before sepsis to 16 mmHg during sepsis and then to 8 mmHg during noradrenaline [2] (Fig. 28.3).

2. Experimental studies

Ang II Noradrenaline Saline

150

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100

* #

NA/Ang II/Saline

Mean Arterial Pressure (mmHg)

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*#

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*# * #

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E.coli

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24 25 26 27 28 29 30 31 32

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E.coli

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1.0

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FIGURE 28.2 Mean arterial pressure, renal blood flow, creatinine clearance, and urine flow during infusion of Escherichia coli from 0 to 32 h and subsequent treatment with angiotensin II (Ang II), noradrenaline (NA), or saline vehicle from 24 to 30 h in unanesthetized sheep (all groups n ¼ 8). Time 0 is the mean of the 24th hour of the baseline period, and times 24e32 h are means of 1-h periods. Data are between-animal mean
SD. Treatmentetime interactions were analyzed by two-way repeated-measures analysis of variance with a Sidak’s multiple comparison post hoc test. *P < .05 vehicle versus Ang II; Y P < .05 vehicle versus NA.

The implications of these findings are that in established septic shock, resuscitation with noradrenaline to improve arterial pressure and renal function may worsen the underlying pathological processes causing AKI, whereas Ang II had no such adverse effects. It is important to note that the changes in intrarenal perfusion and oxygenation occurred independently of changes in renal blood low and oxygen

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CHAPTER 28 Angiotensin in shock: experimental and clinical studies

Ang II Noradrenaline Saline E.coli

2000

1500

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0 0

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50 40 30 20 10

*

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706

24 25 26 27 28 29 30 31 32

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0

*

*

24 25 26 27 28 29 30 31 32

Time (h)

FIGURE 28.3 Renal cortical and medullary tissue perfusion and PO2 during infusion of Escherichia coli from 0 to 32 h and subsequent treatment with noradrenaline (NA), angiotensin II (Ang II), or saline vehicle from 24 to 30 h in unanesthetized sheep (all groups n ¼ 8). Time 0 is the mean of the 24th hour of the baseline period, and times 24e32 h are means of 1-h periods. Data are between-animal mean
SD. Data are between-animal mean
SD. Renal vari ables are presented as absolute values corrected for body weight. Treatmentetime inte ractions were analyzed by two-way repeated-measures analysis of variance with a Sidak’s multiple comparison post hoc test. *P < .05 vehicle versus Ang II; Y P < .05 vehicle versus NA.

delivery, indicating that total kidney measures of oxygenation cannot be used to predict changes in medullary perfusion and oxygenation. It must be acknowledged that in septic AKI there is no identified mechanistic link between renal medullary hypoxia and reduced glomerular filtration rate. It is, however, conceivable that prolonged tissue hypoxia, particularly in metabolically active regions of the kidney such as the renal medulla, induces mitochondrial dysfunction, resulting in increased reactive oxygen species and enhanced renal cellular injury.

3. Clinical studies

3. Clinical studies

3.1 Angiotensin II, an emerging vasopressor for use in sepsis A number of clinical studies over the past 15 years have explored the safety and efficacy of angiotensin II in the treatment of vasodilatory shock, especially in the context of sepsis (Table 28.1). The ATHOS trial was a dose-finding study that included 20 patients with catecholamine-refractory vasodilatory shock and a cardiovascular Sequential Organ Failure Assessment score of at least 4 [29]. Patients were randomized to receive either Ang II or placebo in addition to standard care. Ang II resulted in a marked reduction in noradrenaline dose in all patients (mean noradrenaline dose at 1 h 7.4 mg/min in Ang II vs. 27.6 mg/min in placebo, P ¼ 0.06). No significant difference in mortality was observed between groups (50% in angiotensin II vs. 60% in placebo, P ¼ 1.00). The authors concluded that an initial suitable dose range for Ang II was between 2 and 10 ng/kg/min. Following on from ATHOS, the ATHOS-3 trial was published in 2017. ATHOS-3 was an international, randomized, double-blind, placebo-controlled trial comparing Ang II as an adjunct catecholamine-sparing vasopressor in patients with vasodilatory shock requiring treatment with high-dose catecholamines (defined as 0.2 mg/ kg/min noradrenaline equivalent) [30]. Subtypes of vasodilatory shock included septic shock, postoperative vasoplegia, and other vasodilatory states associated with normal or high cardiac output. A total 163 patients were randomized to receive Ang II by continuous infusion, whereas 158 patients were randomized to placebo. Ang II was found to be superior to placebo with respect to the primary endpoint, which was an increase in mean arterial pressure (MAP) of at least 10 mmHg from baseline (or to a value of at least 75 mmHg) at hour 3 without an increase in the dose of background vasopressors. There was no significant difference in all-cause mortality between groups, but the study was not powered to evaluate this outcome. Secondary analyses of the ATHOS-3 trial have contributed several additional important findings. One post hoc analysis included only those patients from ATHOS-3 who were receiving renal replacement therapy at randomization (n ¼ 45 Ang II and n ¼ 60 placebo) [34]. The authors observed that 28-day survival and MAP response were greater in patients who received Ang II compared with placebo in this subgroup, with an earlier liberation from renal replacement therapy. These findings suggest that Ang II may be particularly beneficial in patients with severe acute kidney injury. Following publication of ATHOS-3 and subsequent approval of Ang II for vasoplegic shock by the US Food and Drug Administration, a number of postmarketing studies have been published. Wieruszewski et al. retrospectively examined the effect of a favorable hemodynamic response to Ang II on mortality in 270 patients admitted to five centers in the United States [32]. The most common cause of shock in their cohort was sepsis (55%), and Ang II was generally prescribed as the third- or fourth-line vasopressor. Approximately two-thirds of patients demonstrated hemodynamic responsiveness to Ang II, defined as the attainment of an MAP

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CHAPTER 28 Angiotensin in shock: experimental and clinical studies

Table 28.1 Summary of results from clinical trials of angiotensin II in patients with vasodilatory shock.

Reference

Design

Population

Chawla et al. [29]

ATHOS trial, a phase 2 randomized controlled trial comparing angiotensin II to placebo

20 patients with catecholaminerefractory vasodilatory shock and a cardiovascular SOFA score 4

Khanna et al. [30]

ATHOS-3 trial, a phase 3 randomized controlled trial comparing angiotensin II with placebo

344 patients with catecholaminerefractory vasodilatory shock

Smith et al. [31]

Multicenter retrospective singlearm observational study

162 patients with catecholaminerefractory vasodilatory shock

Outcomes attributed to angiotensin II Decreased noradrenaline dose at 1h eMean noradrenaline dose 7.4 mg/min in angiotensin II versus 27.6 mg/min in placebo, P ¼ .06 No difference in allcause mortality e50% in angiotensin II versus 60% in placebo, P ¼ 1.00 Greater proportion of patients with MAP response at hour 3 (MAP 10 mmHg increase or 75 mmHg) e69.9% in angiotensin II versus 23.4% in placebo, P < .001 Decreased cardiovascular SOFA score e1.75 in angiotensin II versus 1.28 in placebo, P ¼ .01 No difference in allcause mortality e7 day: 29% in angiotensin II versus 35% in placebo, P ¼ .22 e28 day: 46% in angiotensin II versus 54% in placebo, P ¼ .12 Increased MAP eMean difference at hour 3 compared to baseline 9.3 mmHg (95% CI 6.4 to 12.1), P < .001 Decreased noradrenaline dose

3. Clinical studies

Table 28.1 Summary of results from clinical trials of angiotensin II in patients with vasodilatory shock.dcont’d

Reference

Design

Population

Wieruszewski et al. [32]

Multicenter retrospective singlearm cohort study

270 patients with catecholamine refractory shock

Klijian et al. [33]

Post hoc analysis of ATHOS-3 trial

16 patients who underwent cardiopulmonary bypass (9 angiotensin II; 7 placebo)

Outcomes attributed to angiotensin II eMean difference at hour 3 compared with baseline 0.16 mg/kg/ min (95% CI 0.10 to 0.22), P < .001 Hemodynamic responsiveness (increase in MAP 65 mmHg with a stable total vasopressor dose at hour 3) in 181 patients (67%) Variables associated with hemodynamic response: lower lactate concentration (OR 1.11, 95% CI 1.05 to 1.17, P < .001) and use of vasopressin (OR 6.05, 95% CI 1.98 to 18.6, P ¼ .002) Hemodynamic response was associated with reduced 30-day mortality (HR 0.50, 95% CI 0.35 to 0.71, P < .001) Greater proportion of patients with MAP response at hour 3 (MAP 10 mmHg increase or 75 mmHg) e89% in angiotensin II versus 0% in placebo, P ¼ .0021 Decreased standardof-care vasopressor dose from baseline e76.5% decrease in angiotensin II versus 7.8% increase in placebo, P ¼ .0013 No difference in Continued

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CHAPTER 28 Angiotensin in shock: experimental and clinical studies

Table 28.1 Summary of results from clinical trials of angiotensin II in patients with vasodilatory shock.dcont’d

Reference

Design

Population

Tumlin et al. [34]

Post hoc analysis of ATHOS-3 trial

105 patients who received renal replacement therapy (45 angiotensin II; 60 placebo)

Zangrillo et al. [35]

Single-center retrospective observational study

15 ventilated patients with vasodilatory shock and COVID19-related infection

Leisman et al. [36]

Multicenter retrospective observational study with propensity score matching

29 patients with respiratory failure and catecholaminerefractory vasodilatory shock (10 angiotensin II; 19 control)

Outcomes attributed to angiotensin II 28-day mortality e11% in angiotensin II versus 14.3% in placebo Increased survival at 28 days e53% in angiotensin II versus 30% in placebo, P ¼ .012 Increased discontinuation of RRT by day 7 e38% in angiotensin II versus 15% in placebo, P ¼ .007 Greater proportion of patients with MAP response at hour 3 (MAP 10 mmHg increase or 75 mmHg) e53% in angiotensin II versus 22% in placebo, P ¼ .001 No difference in MAP or urine output over 48 h Increased lactate, creatinine, and SpO2/ FiO2 ratio over 48 h Decreased CRP and FiO2 *Statistical values not provided Decreased noradrenalineequivalent dose over 6h eb 0.04 mg/kg/min/ h (95% CI 0.05 to 0.02) Decreased PaCO2 and d-dimer at 48 h Increased pH at 48 h

3. Clinical studies

65 mmHg with a stable or reduced total vasopressor dose. Patients with lower lactate concentrations and those receiving vasopressin were more likely to have a favorable hemodynamic response to Ang II. On multivariable analysis, the hemodynamic response was associated with reduced likelihood of 30-day mortality. There was no difference in the risk of stage 2 or 3 AKI between groups (76% vs. 77%, P ¼ 0.88) or in the requirement for continuous renal replacement therapy (32% vs. 40%, P ¼ 0.53). There was a nonsignificant decrease in the requirement for renal replacement therapy at 30 days among responders compared with nonresponders (52% vs. 62%, P ¼ 0.18). Smith et al. also conducted a retrospective cohort study of 162 patients with vasodilatory shock who received Ang II at one of five centers in the United States between 2017 and 2020 [31]. The most common cause of shock was sepsis (72%), and almost all patients (94%) were on at least two vasoactive agents prior to initiation of Ang II. The authors reported a significant increase in MAP (mean difference 9.3 mmHg, 95% CI 6.4 to 12.1, P < 0.001) and a reduction in noradrenalineequivalent dose (mean difference 0.16 mg/kg/min) at 3 h following initiation of Ang II. They also found that lower noradrenaline-equivalent dose (60 years) may worsen cognitive outcomes and contribute to tau pathology [165]. A metaanalysis of eight randomized clinical trials evaluating the elderly (69  5.4 (SD) years, 67,476 participants) found a significant reduction in cognitive impairment risk with the use of antihypertensive treatment after a 4-year follow-up [166]. While protection from cognitive impairment was noted, longer-term studies are warranted as dementia is a slowly developing disease. Furthermore, survival bias should also be taken into consideration, as those with severe cognitive impairment may also be at higher risk of mortality [167] and were therefore excluded from analysis. In the later stages of late-life (>80 years), hypertension may have a protective effect from developing dementia via increased cerebral perfusion [168]. These findings indicate that treatment of hypertension is beneficial in preventing cognitive decline, but not beyond 80 years of life. Owing to the protective and deleterious actions of the RAAS, it is possible that the targeting of RAAS components may have differing effects on cognitive outcomes. We will now discuss the evidence of modulating the RAAS in treating cognitive impairment and dementia.

4.1 ACE inhibitors Conventionally, ACE inhibitors are used to reduce systemic blood pressure by blocking the formation of angiotensin II and downstream activation of AT1R. Some ACE inhibitors cross the BBB and may prevent cognitive decline and dementia [160]. However, the use of BBB impermeable ACE inhibitors is associated with

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CHAPTER 31 The role of angiotensin peptides in the brain

greater dementia risk. In animal models, the use of a centrally active ACE inhibitor, perindopril, resulted in cognitive rescue in a mice model of AD [169], whereas noncentrally acting ACE inhibitors, imidapril and enalapril, showed a less potent effect on brain ACE activity and did not elicit cognitive rescue in AD mice. Overall, these findings suggesting that brain ACE activity, and not peripheral ACE activity, plays a role in the development of cognitive impairment. Despite the procognitive effects of ACE inhibitors, there are therapeutic limitations. A retrospective observational study found that AD patients receiving centrally active ACE inhibitors improved cognition within the first 9 months but was not effective thereafter [170].

4.2 AT1R antagonists Current evidence would suggest that ARBs may be useful in mitigating cognitive impairment after stroke. In transgenic mice with higher levels of angiotensin II, daily administration of valsartan for 2 weeks up until the induction of MCAO significantly reduced infarct volume, oxidative stress, and neurological deficits [101]. Furthermore, low dose of olmesartan immediately following stroke reduced neurological deficits, infarct volume, and cerebral edema after MCAO [102]. Even delayed administration of ARBs 7 days poststroke resulted in the prevention of cognitive decline [123]. These findings suggest that through the administration of ARBs, it may be possible to prevent worsened poststroke cognitive outcomes even in the absence of hypertension. In experimental dementia studies, daily administration of candesartan in rodents for 14 days after hypoperfusion surgery resulted in attenuated brain injury and preserved antioxidant capacity [171]. Furthermore, low dose of telmisartan, an ARB that also activates PPARg, prevented cognitive decline and reduced TNF-a expressions in a mice model of AD [172]. Interestingly, PPARg has a profound influence on the RAAS, attenuating deleterious effects while also promoting protective effects [173]. In humans, it was found that losartan was effective in improving cognitive function in the elderly (>75 years) with hypertension, whereas no significant change was seen in those treated with the beta blocker atenolol [174], despite similar effects on blood pressure. These findings suggest that specifically, AT1R antagonists may be a viable candidate for stroke and AD therapy.

4.3 AT2R agonists The AT2R has been extensively studied and has protective effects on many physiological functions [175,176]. Therefore, it is not surprising that selective targeting of AT2R has been examined. Direct AT2R activation has neuroprotective effects for up to 3 weeks poststroke. Administration of C21 resulted in reduced infarct volume and improved neurological outcomes after MCAO [177]. Similar to these findings, delayed administration of C21 24 h poststroke prevented cognitive impairment in aged mice [178]. Furthermore, in diabetic mice, administration of C21 3 days poststroke reduced mortality, the proinflammatory state, and cognitive deficits [179].

4. Modulation of the RAAS as a therapy

Taken together, pharmacological targeting of the AT2R may be a viable therapeutic option for poststroke cognitive impairment. In contrast to stroke-induced cognitive impairment, Royea et al. showed that in a mouse model of AD, delayed treatment of C21 did not improve cognition when assessing mice using the Morris Water Maze [120]. Furthermore, amyloid b peptide distribution in the cortical and hippocampal regions of the brain was not altered by C21. Although no benefits were seen utilizing an AT2R agonist, Royea et al. demonstrated that AT2R antagonist was detrimental to memory, neurovascular coupling, and levels of oxidative stress [120]. These findings suggest that AT2R activation is needed to maintain brain homeostasis but may not be an effective therapy for AD.

4.4 The ACE2/angiotensin (1e7)/MasR axis Similar to AT2R activation counteracting the effects of AT1Rs, ACE2 opposes the effects of ACE. The ACE2/angiotensin (1e7)/MasR axis is the alternate axis that induces antiinflammatory, antioxidative, and vasodilatory properties. ACE2 is used to convert angiotensin II into angiotensin (1e7), which binds to MasR. There is growing interest in utilizing ACE2 and angiotensin (1e7) as novel targets for cardiovascular disease and stroke [105,180,181]. Angiotensin (1e7)-mediated MasR activation has been shown to enhance LTP in the CA1 region of the hippocampus [118], which suggests the MasR may play a role in the consolidation of memory. Additionally, intracerebroventricular administration of angiotensin (1e7) blunted proinflammatory cytokine expressions in the brain, stimulated microglial production of nitric oxide reducing infarct size, and improved motor function after MCAO [103]. Furthermore, infusion of angiotensin (1e7) elicited a neuroprotective effect via suppression of NFkB pathway after MCAO [182]. These findings on the antiinflammatory effects of angiotensin (1e7) directly oppose angiotensin II-induced inflammation, which leads to inhibition of LTP and AD [150]. In hypertension, angiotensin (1e7) infusion increased levels of superoxide dismutase and malondialdehyde activity, while also reducing expression of angiotensin II and AT1R [104]. These effects were associated with a reduction in neuronal apoptosis [104]. Angiotensin (1e7)-mediated MasR activation has also been shown to have a neuroprotective effect on diabetes-induced cognitive impairment, improving cognitive function and reducing amyloid b levels [183]. There is evidence that ACE2/angiotensin (1e7)/MasR axis is downregulated during AD [184,185]; however, more studies are needed to determine whether cognitive function can be restored by stimulating this alternate axis of the RAAS.

4.5 Angiotensin IV and AT4R agonist As discussed before, angiotensin IV can bind to AT2R. However, whether angiotensin IV has the same effects as other AT2R agonists is yet to be determined. Angiotensin IV/AT4R activation has previously been reported to have beneficial effects on motor and cognitive responses [138,186,187]. However, few studies have

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CHAPTER 31 The role of angiotensin peptides in the brain

investigated this angiotensin analog in cerebrovascular or neurodegenerative disease [188]. In AD mice, 1 month of angiotensin IV infusion resulted in improved spatial learning and memory retention, independent of amyloid b pathology [120]. These findings demonstrate that angiotensin IV may be used to mediate cognitive benefits of AD. In a secondary analysis of a SPRINT study, AT2R and AT4R stimulation was associated with lower rates of MCI and dementia [189]. Our understanding of the effects of AT4R/IRAP on cognition during disease is limited, and therefore, more studies are needed to explore the angiotensin IV and its AT4R.

4.6 Other components of the RAAS Angiotensin III has a similar binding profile to angiotensin II and therefore may have the same effects through the AT1R and AT2R [190]. Angiotensin II and angiotensin III stimulate ERK1/2 MAPK via AT1R and promote astrocyte growth; however, at higher dosages, astrocytes were more responsive to angiotensin II [191]. Furthermore, angiotensin III has a higher potency and prolonged activity in neurons from spontaneously hypertensive rats compared with angiotensin II [192]. Previous studies have compared the responses between angiotensin fragments and found that angiotensin II had a significantly longer effect on the AT1R than angiotensin III or IV [193]. Overall, these findings indicate that although angiotensin III has similar actions as its precursor, it has its own unique response within the brain. Angiotensin A/alamandine/MrgD axis is another beneficial arm of the RAAS; the limited research into the role of these novel components have revealed procognitive effects during disease [194,195]. Recently, alamandine treatment alone has been shown to reduce oxidative stress and attenuate renal damage and pressor responses in hypertensive rats [196]. From this data it is tempting to speculate that the reduction in oxidative stress may alleviate the proinflammatory effects hypertension may elicit thereby reducing the risk of developing cognitive impairment. Although little is known about the molecular signaling of alamandine, further understanding of its role in the brain during disease would elucidate whether it is a viable therapeutic option. Finally, the steroid hormone aldosterone is part of the RAAS but not as an angiotensin fragment. Aldosterone is synthesized and secreted from the zona glomerulosa of the adrenal cortex. Higher levels of aldosterone have been implicated in reduced cerebrovascular function [197e199]. Furthermore, individuals exhibiting higher baseline levels of aldosterone may have cognitive benefit from lowering blood pressure [62,162]. The effects on aldosterone on the brain remain an area of ongoing research.

5. Conclusion Neurovascular structures are susceptible to damage from hypertension and stroke. Both induce oxidative stress and neuroinflammation, which are central to cognitive

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Index Note: ‘Page numbers followed by “f ” indicate figures and “t” indicate tables.’

A A disintegrin and metalloprotease 17 (ADAM17), 287, 476 Absorption, 688 Acetyl-CoA carboxylase, 650e651 Acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), 290e291 Acetylcholine (ACh), 683 Achalasia, 683 Actin cytoskeleton dynamics, 737 Activator protein-1 (AP-1), 266e267, 364 Acute hypertension, 134e136 Acute kidney injury (AKI), 700 Acute lung injury (ALI), 293 ACE2 and, 293e294 Acute respiratory distress syndrome (ARDS), 356e357, 399e401, 493e495 Acute tubular necrosis (ATN), 399e401 ADA metalloprotease 17 (ADAM17), 359e360 Adaptive chronic immune system, 378 Adenylate cyclise, 736 Adipocyte dysfunction, 647, 652 hypertrophy, 645 Adipocyte protein-2 (aP2), 652 Adipocyte-specific AT1R-associated protein (ATRAP), 647 Adipogenesis ang (1e7), 652 angiotensin II, 645e647 Adipokines, 643 Adipose plasticity, 645e647 Adipose tissue, 643 b-adrenergic blockers, 362 b3-adrenergic receptor, 648e650 Adrenocortic otropic hormone (ACTH), 629e630 Adult mammals brain, 457 Age-related macular degeneration (AMD), 432e433 Agonistic autoantibodies against AT1R (AT1-AA), 523 Alamandine (ALA), 87e88, 121e122, 427e428, 625, 657, 749 Alatensins, 624e625

Aldosterone, 154, 360e361 activates mineralocorticoid receptors, 356 inhibitor, 360e361 release, 356 Aliskiren, 358e359 Alveolar type II cells, 396e397 Alzheimer’s disease (AD), 109, 457, 547, 550e551, 568e569, 758 American Heart Association/American College of Cardiology (AHA/ACC), 275e276 Amino acids, 119, 322e323, 392 homeostasis, 681e682 Amino peptidase, 117 a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), 756 Aminopeptidase A (APA), 109, 242, 597e598, 654, 670e671, 750 Aminopeptidase M (APM), 242 Aminopeptidase N (APN), 109, 597e598, 656, 670e671, 750 Amniotic fluid, 193 Amniotic sac, 180 AMP-activated protein kinase (AMPK), 43e45, 238e240, 288e289, 653 Amphetamine facilitatory effect, 720 Amphetamine sensitization, 720 Amyloid b (Ab), 112, 550 Analogs of Ang-(1e7) with anticancer properties, 585 Angiotensin (Ang), 155, 180, 422e423, 474, 624, 669e670, 752e754 ACE2, 475e478 additional, 654e658 alamandine, 657 Ang III or Ang (2e8), 654e656 Ang IV or Ang (3e8), 656e657 Ang (2e8), 654e656 Ang (3e8), 656e657 Ang-(1e9), 88e89 angiotensin receptor inhibition and reprogramming of tumor microenvironment, 529e530 angiotensin-converting enzyme, 80, 268, 684, 717 inhibition, 739e740 ole in inflammation, 80

775

776

Index

Angiotensin (Ang) (Continued) angiotensin-treated rats, 159e160 angiotensindclinical and therapeutical implications, 275e276 association of angiotensins with clinical relevance in different cancers, 514e529 breast cancer, 525e526 cervical cancer, 521 colorectal cancer, 529 esophageal cancers and Barrett’s esophagus, 522e523 gastric cancer, 528 hepatocellular carcinoma, 523e525 lung cancer, 526e527 ovarian cancer, 523 pancreatic cancer, 526 prostate cancer, 521e522 association of angiotensins with clinical relevance in different cancers, 514e529 RAS components in different malignancies, 515te520t challenges associated with angiotensin inhibitors, 530e531 clinical studies, 707e713 Ang II treatment for COVID-19, 711 angiotensin I/II ratio and rennin, 712e713 angiotensin II, emerging vasopressor for use in sepsis, 707e711 angiotensin II treatment for postoperative hypotension, 711e712 cost-effectiveness, 712 safety of angiotensin II, 712 in context of pain, 601e602 in development of cognitive impairment, 754e756 hypertension, 754e755 stroke, 755e756 effects of SARS-CoV-2 infection, 479e481 endothelial dysfunction, 264e265 experimental studies, 700e706 angiotensin II in early experimental sepsis, 701e702 effects of Ang II on intrarenal perfusion and PO2 in established sepsis, 704e706 intrarenal perfusion and oxygenation in sepsis, 703e704 model of sepsis, 700e701 renal bioenergetics, 703 sepsis, 700 fragments, 753 genetic polymorphisms, 478e479

global burden of atherosclerotic vascular disease, 263 inhibition of RAS components and impact on cancer progression, 530 interaction between angiotensin and mediators of atherosclerotic process, 270e275 and major receptors in pain, role of, 602e610 and cancer pain, 606e608 and fibromyalgia, 609e610 and inflammatory pain, 605e606 and muscle pain, 608e609 and neuropathic pain, 603e605 in nocifensive pain, 602 and sickle celleassociated pain, 610 RAS, 265e266 renineangiotensinealdosterone system, 508e514 primary components of RASeangiotensin pathway, 508e513 RAS components and cancer, 513e514 role of angiotensin in pathophysiology of atherosclerotic plaques, 266e270 SARS-CoV-2, 474e475 and types, 512 angiotensin I, 512 angiotensin II, 512 Angiotensin A (Ang A), 87 Angiotensin convertase inhibitors (ACE-I), 46 Angiotensin converting enzyme (ACE), 733 Angiotensin I (Ang I), 22e23, 153e154, 335, 355e356, 390, 423e425, 512 ratio, 712e713 Angiotensin I type 1receptor (AT1R), 749e750 Angiotensin II (Ang II), 22, 77, 107, 158, 213, 235, 266, 317e318, 375, 423e425, 491e492, 508, 644e650, 699, 717, 733 in abnormal water and salt handling in PKD, 738e739 ACE inhibitors/ARB in clinical trials, 739e741 actions of angiotensin II within spinal cord, 8e11 AT1R within spinal cord, 8e9 changes in spinal cord AT1R during heart failure, 11 regulation of sympathetic nerve activity by AT1R within spinal cord, 9e11 adipogenesis, 645e647 Ang II and toll-like receptors within central nervous system, 380 Ang II cross-talk with cystogenic pathways, 736e737, 738f Ang II-induced microglia activation, 379 angiotensin II-induced contractions, 685

Index

angiotensin type 1 receptor, 81e82 angiotensin type 2 receptors, 83e84 blockade of central angiotensin type 1 receptor decreases SNA, 4e6 blocking activity of, 323e324 and bradykinin system, 380e383 browning, 648e650 RAS effects on WAT browning, 649f central regions that respond to angiotensin II, 6e8 actions of Ang II within area postrema, 8 actions of angiotensin II within rostral ventral lateral medulla, 7e8 role of paraventricular nucleus of hypothalamus in HF, 7 circulating levels of angiotensin II in heart failure, 3 classical actions of ANG II in kidney, 237e238 cross-talk with cystogenic pathways, 736e737 in diabetic nephropathy, 167e169 in early experimental sepsis, 701e702 emerging vasopressor for use in sepsis, 707e711 evidence of RAS dysregulation in PKD, 734e736 in extrarenal disease in PKD, 739 glucose metabolism, 648 increases bloodebrain barrier disruption in hypertension, 377 inflammation, 647e648 on intrarenal perfusion and PO2 in established sepsis, 704e706 in ischemia nephropathy, 165e166 lipid storage, 645 in progression of ARVD, 162e163 ratio, 712e713 and renal fibrosis, 246e251 and renal growth, 243e244 and renal inflammation, 245e246 in renovascular hypertension, 158e160 role of, 3e8 role of central angiotensinergic mechanisms, 4 safety of, 712 treatment for COVID-19, 711 treatment for postoperative hypotension, 711e712 Angiotensin III, 242, 450e451, 654e656 Angiotensin IV (Ang IV), 24e25, 107, 242, 656e657 and AT4R agonist, 761e762 receptor, 450e451 Angiotensin peptides, 21, 28, 109, 345 angiotensin and regulation of neurovascular structure and function, 752e754

angiotensin in development of cognitive impairment, 754e756 hypertension, 754e755 stroke, 755e756 angiotensin receptors, 752 brain renineangiotensin system affecting cardiovascular regulation, 31e33 with autonomic nervous system, 25e28 in cardiovascular regulation in heart failure, 38e40 in cardiovascular regulation in hypertension, 33e38 in regulation of watereelectrolyte balance, 28e30 brain targeting renineangiotensin system inhibitors in cardiovascular diseases, 47e48 contributions to memory, learning, and cognitive impairment, 756e759 cognitive impairment and dementia, 758e759 memory and learning, 756e758 formation of angiotensin peptides, 749e752, 751f metabolism, 495 modulation of RAAS as therapy for cognitive impairment and dementia, 759e762 ACE inhibitors, 759e760 ACE2/angiotensin /MasR axis, 761 angiotensin IV and AT4R agonist, 761e762 AT1R antagonists, 760 AT2R agonists, 760e761 components of RAAS, 762 renineangiotensin system in diabetes mellitus and metabolic syndrome, 41e42 organization, 21e25 in pathogenesis of myocardial infarction, 42e46 Angiotensin receptor blockers (ARBs), 3, 46, 48, 187, 357, 359e360, 389, 456, 482, 507e508, 598e599, 626e628, 734e735 in clinical trials, 739e741 in diabetic nephropathy, 167e169 Angiotensin receptors, 29, 752 Angiotensin system inhibitor (AS-I), 530 Angiotensin type 1 (AT-1), 265e266, 699 Angiotensin type 1 receptor (AT1R), 77, 79, 81e82, 107, 265e266, 356, 425, 626e628, 644, 717 angiotensin II type 1 receptor role in inflammation, 82 antagonists, 760 blockers, 133e137 blocking activity of, 323e324

777

778

Index

Angiotensin type 1 receptor (AT1R) (Continued) in dopamine imbalance, 720e726 astrocytes in ketamine-induced dopaminee glutamate imbalance model, 720e721 experimental design, 722f study of AT1-R involvement in long-lasting ketamine effects in dorsal striatum, 722e726 gene, 456 involvement in long-lasting ketamine effects in dorsal striatum, 722e726 experimental design, 722f role in glial cells, 455e459 within spinal cord, 8e9 changes in spinal cord AT1R during heart failure, 11 regulation of sympathetic nerve activity by, 9e11 Angiotensin type 2 (AT2), 265e266 Angiotensin type 2 receptor (AT2R), 83e84, 107, 340, 356, 425, 598, 644 activation in renovascular hypertension, 160e161 angiotensin II type 2 receptors role in inflammation, 83e84 in glial cells, 455e459 Angiotensin type 4 receptor (AT4R), 24e25, 109, 427, 644, 682 Angiotensin-(1e7), 85e86, 567e570, 580e581, 650e654 adipogenesis, 652 analogs of Ang-(1e7) with anticancer properties, 585 browning, 653e654 clinical research, 581e584 clinical trials in cancer patients administered Ang-(1e7), 582e583 with standard-of-care chemotherapy, 583e584 in control of proinflammatory reactive gliosis, 459e460 glucose metabolism, 652e653 inflammation, 652 limitations of Ang-(1e7) as drug, 584e588 lipid storage, 650e651 and mas receptor role in inflammation, 86e87 Mas1 axisdtarget for cancer drug development, 570e573 Mas1 receptor axis, 567e570 biological processes mitigated by, 569f enzymatic synthesis and catabolism of, 568f and Mas1, 512 potentiating opposing function of, 324 preclinical research, 573e581

Ang-(1e7)dcombination therapy, 580e581 animal models, 576e579 in vitro studies, 573e576 Angiotensin-converting enzyme (ACE), 3, 23, 77, 107, 153e155, 180, 213, 235, 265, 317e318, 355e356, 376e377, 389, 391, 419, 545e546, 567e568, 597e598, 624, 626e628, 644, 669e670, 681, 750 blocking activity of, 323e324 Angiotensin-converting enzyme 1 (ACE1), 22, 449 Angiotensin-converting enzyme 2 (ACE2), 22, 84e86, 238e240, 285e286, 324, 389, 391, 419e421, 474e478, 491e492, 512, 613, 681e682 ACE2 as “functional receptor” during viral entry into cells, 392 ACE2 knock-in mutation in mice, 495 ACE2 knockout mice and rats, 493e495 ACE2 role in inflammation, 85e86 ACE2-positive cells, 394 ACE2/Ang- (1e7) /mas receptors role in cerebrovascular diseases, 552e557 ACE2/Ang-(1e7)/mas receptors role in cerebrovascular diseases, 552e557 ACE2/Ang-(1e7)/mas receptors role in mood disorders, 551e552 ACE2/Ang-(1e7)/mas receptors role in neurodegenerative disorders, 547e551 ACE2/angiotensin/MasR axis, 761 activation of, 628e629 activators, 123e125 and acute lung injury, 293e294 Alzheimer’s disease, 550e551 and asthma, 289e290 cell typeespecific overexpression of ACE2 in mice, 496 in central nervous system pathophysiology, 547e557 in central nervous system physiology, 546e547 cerebrovascular hemorrhagic disorders, 555e556 cerebrovascular ischemic disorders, 553e555 and chronic obstructive pulmonary disease, 292e293 conditional ACE2 knockout, 495 and COVID-19, 294e296 gene, 286 human ACE2 overexpression in mouse brain, 496 human ACE2 overexpression in mouse heart, 497 human ACE2 overexpression in mouse podocytes, 497

Index

human ACE2 overexpression in rat vascular smooth muscle, 497 humanized ACE2 expression in mouse/coronavirus infection models, 497e498 interaction between S protein and ACE2, 476e477 knock-in mutation in mice, 495 knockout mice, 493e495 knockout rats, 493e495 localization of ACE2 in various tissues, 393e399 and lung cancer, 291e292 Parkinson’s disease, 548e549 potentiating opposing function of, 324 and pulmonary fibrosis, 290e291 and pulmonary hypertension, 287e289 RAS/RAAS cascade, 390e391 regulation of, 477e478 role of ACE2 in lung repair and regeneration, 296e297 transgenic rodent models with altered ACE2 expression, 494t traumatic brain injury, 556e557 up-and down regulation of, 399e406 expression of AT1, AT2, and MAS receptor, 406 possible (down) regulation of ACE2 after binding SARS-CoV-2, 406 two axes of RAAS cascade, 402 Angiotensin-converting enzyme inhibitors (ACEIs), 47e48, 86, 128e132, 268e269, 357, 381, 389, 425e427, 507e508, 626e628, 669e670, 699, 711e712, 759e760 in clinical trials, 739e741 in diabetic nephropathy, 167e169 for stress-associated conditions, 629e632 Angiotensinergic systems, 718 Angiotensinogen (Agt), 22e23, 27, 79, 109, 153e154, 182, 320e323, 345, 347e348, 425, 507e508, 512, 671, 673, 717 expression in reactive astrocytes, 454 Angiotensinogenase, 513 Angiotonin, 597 Angle-closure glaucoma, 429 Animal models, 576e579 Anteroventral third ventricle (AV3V), 8 Anteroventral third ventricle wall (AV3V), 29 Anti-RAS drugs, 674 Anti-VEGF therapies, 434 Antiangiogenic drugs (AADs), 525 Anticancer properties, analogs of Ang-(1e7) with, 585

Antidiuretic hormone (ADH), 110, 669e670, 736 Antihypertensive drugs, 317, 759 Antihypertensive therapy, 425e427 Antiinflammatory drug, 576e577 Antiinflammatory effects, 761 Antioxidants, 270 Antisense oligonucleotides (ASOs), 320, 735 Antithrombotic therapy, 712 Anxiety disorders, 623e624, 631 clinical evidence, 629e632 contemporary renineangiotensin system, 624e625 new therapeutic strategies, 623e624 RAS components as therapeutical targets for stress-associated conditions, 626e629 activation of ACE2/angiotensin- (1e7) /mas receptor axis, 628e629 blockade of classical axis, 626e628 vascular effects to behavioral modulation, 625e626 Apical brush-border membrane, 691 Apolipoprotein E (ApoE), 493 Aquaporin 2 (AQP2), 736 Aquaporin-4 (AQP-4), 452 Aqueous humor, 423 Aqueous humor homeostasis, 423 Arachidonic acid, 216 Area postrema (AP), 24 Arginine vasopressin (AVP), 188e190 b-arrestins (barr), 599 Arterial blood pressure, 34e35 Ascorbic acid, 119e121, 136e137 Asthma, ACE2 and, 289e290 Astrocytes, 718e719 astrocytes in dopamine-related mental disorders, 718e720 major depression, 719 Parkinson’s disease, 719 schizophrenia, 720 AT1-R in dopamine imbalance, 720e726 astrocytes in ketamine-induced dopaminee glutamate imbalance model, 720e721 study of AT1-R involvement in long-lasting ketamine effects in dorsal striatum, 722e726 in dopamine-related mental disorders, 718e720 essential homeostatic cells in CNS that respond to brain RAS activation, 451e453 hypertrophy, 720 in ketamine-induced dopamineeglutamate imbalance model, 720e721 ramification, 723

779

780

Index

Astrocytes (Continued) stellation, 725e726 Astroglia, 452 Astromicrogliosis, 556e557 AT1 receptoreassociated protein (ATRAP), 241, 598 AT1R autoantibodies (AT1-AAs), 196 AT2R agonists, 125e127, 760e761 AT2R gene (Agtr2), 605 Atheroma, 161 Atheromatous renovascular disease (ARVD), 161e164 angiotensin II in progression of, 162e163 pathophysiology of, 161e162 role of ACE-I/ARBs in, 163e164 Atherosclerosis, 161, 219, 263, 268, 271 local bone marrow renineangiotensin system in, 217e219 Atherosclerotic plaques, role of angiotensin in pathophysiology of, 266e270 Atherosclerotic process, interaction between angiotensin and mediators of, 270e275 Atherosclerotic renovascular disease (ARVD), 167 Atherosclerotic vascular disease angiotensindclinical and therapeutical implications, 275e276 endothelial dysfunction, 264e265 global burden of atherosclerotic vascular disease, 263 interaction between angiotensin and mediators of atherosclerotic process, 270e275 RAS, 265e266 role of angiotensin in pathophysiology of atherosclerotic plaques, 266e270 Atrial natriuretic peptide (ANP), 364 Autoantibodies, 272 Autocrine functions, 181, 213, 681 Autonomic cardiovascular control, 625 Autonomic nervous system, brain renine angiotensin system with, 25e28 Autosomal dominant PKD (ADPKD), 733 Autosomal recessive PKD (ARPKD), 733

B Barrett’s esophagus, 522e523 Basal mucosal alkaline secretion, 690e691 Basic fibroblast growth factor (bFGF), 270 Basolateral membrane, 736 Beta-adrenergic receptor antagonists (b-blockers), 361e362 Beta-blockers, 361e362

Beta-galactosidase (beta-Gal), 23 Beta-P4H, 290e291 Bifidobacterium longum, 692 Bioactive peptides, 717 Bipolar disorder (BD), 551 Bladder urinary, 704 Blastocyst, 179e180 Bleomycin, 290e291 Blockade of classical axis, 626e628 b-blockers, 361e362 Blood CD45-positive cells, 213 Blood cell production, 215e216 Blood flow, 161e162, 701 Blood mononuclear cells, 214 Blood pressure (BP), 152e153, 156, 335, 355, 375, 699, 737 Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC), 318e319 Blood vessels, 601, 681 Blood-borne Ang II, 375 Bloodeaqueous barrier, 422e423 Bloodebrain barrier (BBB), 3, 24, 109, 375, 449e450, 625e626, 749 angiotensin II increases bloodebrain barrier disruption in hypertension, 377 Blooderetinal barrier, 422 Body mass index (BMI), 91e92, 643 Bone marrow, 220 bone marrowederived hematopoietic stem cells, 214 bone marrowerelated endothelial progenitor cells, 219e220 norepinephrine, 220 response-to-lipid hypothesis, 217e219 Bowman’s capsule, 395 Bradykinin (BK), 188e190 angiotensin II and, 380e383 Bradykinin receptor B1 (BKB1R), 293e294 Brain, 119e121, 343e344, 449e450 ACE inhibitors, 47e48 angiotensin II and action within brain during hypertension angiotensin II, innate immune system, neuroinflammation, and hypertension, 378e380 angiotensin II and bradykinin system, 380e383 angiotensin II increases bloodebrain barrier disruption in hypertension, 377 hypertension and angiotensin II, 376e377 angiotensin receptor blockers, 48 glial cells, 551e552

Index

reactive astrogliosis generic response to brain injury, 453e454 targeting renineangiotensin system inhibitors in cardiovascular diseases, 47e48 Brain natriuretic peptide (BNP), 275 Brain RAS, 26e27 in cardiovascular regulation in heart failure, 38e40 Brain renineangiotensin system affecting cardiovascular regulation, 31e33 COVID-19, 32e33 stress and depression, 31e32 with autonomic nervous system, 25e28 in cardiovascular regulation in hypertension, 33e38 in injured brain angiotensin (1e7)/MasR pathway in control of proinflammatory reactive gliosis, 459e460 angiotensinogen expression in reactive astrocytes, 454 AT1R and AT2R role in glial cells, 455e459 RAS and brain renineangiotensin system, 449e451 reactive astrogliosis generic response to brain injury, 453e454 RAS and, 449e451 in regulation of watereelectrolyte balance, 28e30 kidney and gastrointestinal system, 29e30 regulation of sodium and water intake, 28e29 Breast cancer, 512, 525e526, 582 Bronchoalveolar stem cells (BASCs), 296e297 Browning Ang (1e7), 653e654 Angiotensin II, 648e650 RAS effects on WAT browning, 649f Brush-border membrane peptidase, 681 Burst-forming unit-erythroid (BFU-E), 217e219 Bypass loops for RAS activation in cancer, 513

C c-Jun N-terminal kinases (JNK), 24 c-mas gene, 238e240 C-terminal domain of PC2, 736 Ca2+-calmodulin-dependent protein kinases (CaM kinases), 82 Calcium channels blockers (CCBs), 739e740 Cancer, 513e514, 642 cells, 570 clinical trials in cancer patients administered Ang-(1e7), 582e583

Mas1 axisetarget for cancer drug development, 570e573 pain, 606e608 progression, 530 treatment, 580 Cancer-associated fibroblast (CAFs), 529 Cancer-induced bone pain (CIBP), 606e607 Candesartan, 136e137, 522 Captopril treatment, 625e626 Carboximonopeptidase, 624e625 Carboxyl groups, 128e130 Carboxypeptidase A (CxA), 88 Carboxypeptidase M (CPM), 380e381, 475e476 Carboxypeptidases (CPN), 380e381 Cardiac beta adrenergic receptors, 628 Cardiac disease, 741 Cardiac fibrosis, 250 Cardiac function, 567 Cardiac modalities, 514 Cardiac norepinephrine spillover, 2 Cardiac output increases, 185 Cardiac remodelling, 359e360 Cardiac sympathetic neurons, 624 Cardiac b-adrenoceptors, 3 Cardiopulmonary bypass, 703 Cardiovascular centers, 36 Cardiovascular centers, 38e39 Cardiovascular criteria, 701e702 Cardiovascular diseases (CVD), 31, 263, 318, 323, 642, 734 brain targeting renineangiotensin system inhibitors in, 47e48 Cardiovascular drugs, 265 Cardiovascular functions, 597e598, 681 Cardiovascular homeostasis, 749 Cardiovascular regulation brain renineangiotensin, 31e33 in heart failure, 38e40 in hypertension, 33e38 Cardiovascular risk, 318e319 Cardiovascular Sequential Organ Failure Assessment, 707 Cardiovascular system, 186e187, 355, 480, 669e670 Cas9 technology, 493 Catecholamines, 362 b-catenin, 736e737 Cathepsin, 182 Cathepsin A (CpA), 88 Caudal-related homeobox gene 2 (CDX2), 214 Cell membrane, 389

781

782

Index

Cell typeespecific overexpression of ACE2 in mice, 496 Cellular morphology, 720e721 Cellular NADPH oxidase, 268e269 Central angiotensin type 1 receptor decreases SNA, blockade of, 4e6 Central angiotensinergic mechanisms, role of, 4 Central brain regions, 8e9 Central nervous system (CNS), 33, 81, 110, 271, 355, 375, 449e450, 598e599, 624, 717 ACE2/Ang- (1e7) /mas receptors role in cerebrovascular diseases, 552e557 cerebrovascular hemorrhagic disorders, 555e556 cerebrovascular ischemic disorders, 553e555 traumatic brain injury, 556e557 ACE2/Ang-(1e7)/mas receptors role in mood disorders, 551e552 ACE2/Ang-(1e7)/mas receptors role in neurodegenerative disorders, 547e551 Alzheimer’s disease, 550e551 Parkinson’s disease, 548e549 Ang II and toll-like receptors within, 380 pathophysiology, 547e557 physiology, 546e547 Central renineangiotensin system, cooperation of, 21e25 Centrosome, 598 Cerebral blood flow, 550 Cerebral endothelial cells, 752e753 Cerebrospinal fluid, 47 Cerebrovascular diseases, 552e553, 749 ACE2/Ang-(1e7)/mas receptors role in, 552e557 Cerebrovascular hemorrhagic disorders, 552e553, 555e556 Cerebrovascular ischemic disorders, 553e555 Cervical cancer, 521 Cervical intraepithelial neoplasia (CIN), 521 Chemotherapeutic drug, 569e570 Chemotherapy, 603 Chemotherapy-induced peripheral neuropathy (CIPN), 607e608 Chinese hamster ovary cells (CHO), 88e89 Chorionic villi, 190e192 Choroid vessels, 422e423 Chromosome 6, 733 Chronic constriction injury (CCI), 605 Chronic fatigue syndrome (CFS), 609 Chronic hypoxia, 287e288

Chronic inflammatory disease, 263 Chronic kidney disease (CKD), 157e158, 235, 473, 550, 734 Chronic obstructive pulmonary disease (COPD), 291e292 ACE2 and, 292e293 Chronic pain, 601 Chymase, 624e625 Ciliopathy, 734 Circulating RAAS, 182 Circumventricular organs (CVOs), 24, 375, 717, 754e755 Cis-3-(aminomethyl) cyclobutane carboxylic acid (ACCA), 119, 586e587 Classical arm, 644 Classical pathway, 390 Clinical trials in cancer patients administered Ang-(1e7), 582e583 Closed-angle glaucoma, 429e430 Coagulation system, 657 Cognition-altering diseases, 756e757 Cognitive impairment, 756e759 and dementia, 758e759 and dementia, modulation of RAAS as therapy for, 759e762 memory and learning, 756e758 Colon, 692 tissue, 398 Colonic epithelial cells, 672 Colonic fibrosis, 674 Colonic function, 686e687 Colorectal cancer (CRC), 529 Combination therapy, 580e581 Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis (CAMELOT), 276 Complete Freund’s adjuvant (CFA), 605 Complex regulatory networks, 249e250 Congenital heart disease (CHD), 289 Contemporary renineangiotensin system, 624e625 Coronary artery disease, 263 Coronavirus disease 2019 (COVID-19), 32e33, 294e295, 324, 357, 434e436, 473, 478, 492e493, 613e615 ACE2 and, 294e296 ACE2, 475e478 Ang II treatment for, 711 effects of SARS-CoV-2 infection, 479e481 genetic polymorphisms, 478e479 infection models, 419e421, 497e498

Index

local bone marrow renineangiotensin system and, 220e222 mouse models, 492e493 pandemic, 623e624, 642, 670e671 SARS-CoV-2, 474e475 Corticosteroids, 364 Corticotropin-releasing factor, 626e628 Corticotropin-releasing hormone (CRH), 496, 629e630 Counterregulatory arm, 644 Counterregulatory axis, 546e547 Crohn’s disease (CD), 672 Cutaneous-induced inflammation, 606 Cyclic adenosine monophosphate (cAMP), 568e569 Cyclic AMP response elementebinding protein (CREB), 266e267 Cyclic guanosine monophosphate (cGMP), 683 Cyclodextrins, 121 Cyclooxygenase-2 (COX-2), 43e45, 526e527, 575, 652 Cyst growth, 735 Cystic kidney disease, 733 Cystogenesis process, 735 Cystogenic pathways, Ang II cross-talk with, 736e737 Cytokeratin 18 (K18), 497 Cytokine, 79 storm, 294e295, 359 Cytomegalovirus (CMV), 496 Cytotrophoblasts, 190e192

D Damage-associated molecular patterns (DAMPs), 453 Decarboxylase (DC), 597e598 Decidua, 179e180 RAS components in decidua in normal pregnancy, 193e194 Deciduas, 190e194 Delta ACE2 (dACE2), 287 Dementia, 758e759 modulation of RAAS as therapy for cognitive impairment and, 759e762 Deoxycorticosterone acetate (DOCA), 89, 572, 754 DOCA-salt rat model, 572 DOCA-salt treatment, 750e752 Deposition of extracellular matrix, 235 Depression, 31e32, 631e632, 719 Des-Arg10-KD (DAKD), 380e381 Des-Arg9-BK (DABK), 293e294, 380e381

Dextran sodium sulfate (DSS), 673 Diabetes mellitus (DM), 168e169, 272, 318, 431e432, 478 renineangiotension system in, 41e42 Diabetes mellitus type 2 (DM2), 642 Diabetic kidney disease, 167 Diabetic nephropathy, 167e169, 692 angiotensin II, ACE inhibitors, and ARBs in, 167e169 pathogenesis of, 167 Diabetic retinopathy (DR), 429, 431 1,2-diacylglycerol (DAG), 82 Diastolic dysfunction, 275 Dichlorofluorescein (DCF), 336e340 Diet-induced obesity models, 647 Digestive system, 598e599 colon tissue, 398 pancreas tissue, 397 tissue in, 397e399 tongue mucosa and salivary gland, 398e399 Diminazene aceturate (DIZE), 124e125, 287e288, 431, 550e551, 629 2,4-dinitrobenzenesulfonic acid (DNBS), 688 Dipeptidyl carboxyl peptidase, 624 Dipeptidyl peptidase (DPP), 119 Dipeptidylaminopeptidase III (DPP3), 656 Diphenyliodonium (DPI), 336e340 Direct renin inhibitors (DRIs), 317e318, 358e359 4,40 -disulfanediylbis-(3-ammoniobutane-1-sulfonate), 117 Dopamine (DA), 717e718 Dopamine 1 receptor (D1R), 112 Dopamine imbalance, AT1-R in, 720e726 Dopamine-related mental disorders. See also Anxiety disorders astrocytes in, 718e720 major depression, 719 Parkinson’s disease, 719 schizophrenia, 720 Dopaminergic cells, 717e718 Dopaminergic neurons, 549 Dopaminergic neurotransmission, 628 Dopaminergic synapse, 719 Dorsal motor nucleus of vagus (DMNV), 24 Dorsal root ganglia (DRG), 603e604 Dorsal striatum, 721 study of AT1-R involvement in long-lasting ketamine effects in, 722e726 Dose-limiting toxicity (DLT), 582 Doxorubicin (Dox), 580e581 Drugs, 430

783

784

Index

Drugs (Continued) development process, 573 development strategies targeting renine angiotensin system, 113e122 MasR agonists, 113e122 for hypertension, 318e324 limitations of Ang-(1e7) as, 584e588 renin, 319e324 Dual-specificity phosphatase-1 (DUSP-1), 570e571 Duchenne muscular dystrophy, 609 Duodenal mucosal bicarbonate secretion, 690e691 Dysfunctional autonomous nervous system output, 219e220 Dyslipidemia, 272

E Electron paramagnetic resonance (EPR), 599 Embryologic development, 717e718 Embryonic stem cells (ES cells), 493, 495 Emotional stress, 623e624 and anxiety disorders, 623e624 clinical evidence, 629e632 contemporary renineangiotensin system, 624e625 new therapeutic strategies, 623e624 RAS components as therapeutical targets for stress-associated conditions, 626e629 activation of ACE2/angiotensin- (1e7) /mas receptor axis, 628e629 blockade of classical axis, 626e628 vascular effects to behavioral modulation, 625e626 EMPADINE, 603 EMPHENE, 603 Endocrine functions, 77, 546, 644 Endocrine system, 507e508, 602, 681 controlling salt, 185 Endogenous ligands, 598, 752 Endothelial cells (ECs), 162e163, 264e266, 272, 287, 717 Endothelial dysfunction, 264e265, 270, 275 Endothelial nitric oxide synthase (eNOS), 35, 553e554 Endothelial progenitor cells (EPCs), 296e297 Endothelial selectin (E-selectin), 43e45 Endothelial to mesenchymal transition (EMT), 160 Endothelin A receptor autoantibodies (ETAR-AAs), 196e197 Endothelin-1 (ET-1), 196, 270, 274, 553, 572

Endothelin-1 type A receptor (ETAR), 272 Endothelin-activated protein kinase, 570e571 Endothelium, 161, 752e753 dysfunction, 264 Energy storage, 643 Enhanced green fluorescent protein (eGFP), 23 Enteric neurons, 681e682 Envelope protein (E protein), 474 Enzymatic cleavage, 567e568 Enzyme, 425 Enzyme-replacement therapy, 608 Epidemiological data, 550 Epidermal growth factor receptor (EGFR), 241 Epithelial functions, 688e692 esophagus and stomach, 689e690 large intestine, 692 small intestine, 690e692 Epithelial sodium channel (ENaC), 188e190 Epithelial-to-mesenchymal transition (EMT), 246, 575e576, 737 Epogen, 580 Erythropoietin (EPO), 525 Escherichia coli, 700e701 Esophageal adenocarcinoma (EAD), 522 Esophageal cancers, 522e523 Esophageal mucosa, 682 Esophageal sphincter, 683 Esophageal squamous cell carcinoma (ESCC), 522 Esophagus, 683e684 and stomach, 689e690 Essential hypertension, 194 Estimated glomerular filtration rate (eGFR), 734e735 17-b-estradiol, 477e478 ETA receptor (ETAR), 270 European Society of Cardiology (ESC), 275e276 European trial on Reduction Of cardiac events with Perindopril among patients with stable coronary Artery disease (EUROPA), 276 Experimental studies, 700e706 angiotensin II in early experimental sepsis, 701e702 effects of Ang II on intrarenal perfusion and PO2 in established sepsis, 704e706 intrarenal perfusion and oxygenation in sepsis, 703e704 model of sepsis, 700e701 renal bioenergetics, 703 sepsis, 700 Extracellular calcium influx, 684

Index

Extracellular domain (ECD), 406 Extracellular matrix (ECM), 246e247, 296e297, 530, 737 Extracellular matrix metalloproteinase inducer (EMMPRIN), 43e45 Extracellular senile plaque, 550 Extracellular signaleregulated kinases (ERK), 81, 670e671 Extracellular signaleregulated protein kinases 1 and 2 (ERK1/2), 24, 79, 240, 570, 645e647 Extracellular space, 345, 452 Extrarenal disease in PKD, Ang II in, 739 Extravillous trophoblasts (EVTs), 190e192 Eye components of RAS in eye, 420te421t eye diseases and local renineangiotensin system, 429e436 human eye’s anatomy and physiology, 421e423 local renineangiotensin system in, 428e429 renineangiotensin system, 423e428

F Fatty acid synthase (FAS), 645 Fatty acidebinding protein 4 (FABP4), 645 Fetal growth changes in maternal circulating RAAS in pregnancies associated with FGR, 198e200 changes in placental RAS expression in pregnancies associated with FGR, 200e201 role of RAS in regulating fetal growth, 198e201 Fetal growth restriction (FGR), 180, 198 Fetal membranes, 180, 190e194 fetal sex, gestation, and labor on expression of RAS in, 193e194 gestation and labor on expression of RAS in, 193 Fetal metabolism, 180 Fibroblast growth factor 21 (FGF21), 653 Fibroblast-specific protein 1 (FSP-1), 291 Fibromuscular dysplasia (FMD), 155e156 Fibromyalgia, 609e610 syndrome, 609e610 Fibrosis, 246, 275, 571e572 Fibrous tunic, 421 Filgrastim, 583e584 Filtration fractions, 738e739 Fletcher trait, 382e383 Fluid homeostasis, 355, 752 Fluid volume balance, 152e153 Focal adhesion kinase (FAK), 287e288, 513e514 Forkhead helix O (FoxO), 653 Fragmentation, 739

Free fatty acids (FFAs), 643e644 “Functional receptor” during viral entry into cells, ACE2 as, 392

G G proteinecoupled angiotensin receptors, 107e108 G proteinecoupled receptor (GPCR), 81, 182, 342e343, 356, 391, 525, 568, 598, 625, 752 Gall bladder carcinoma (GBC), 512 Gastric cancer, 528 cell, 528 Gastric mucosa, 625e626 Gastric secretion, 690 Gastric smooth muscle cells, 684 Gastroesophageal reflux disease (GERD), 522 Gastrointestinal muscular wall, 682 Gastrointestinal smooth muscle, 682 Gastrointestinal system, 29e30, 481 Gastrointestinal tract (GIT), 136e137, 672, 682 Gene expression, 738e739 Gene Expression Omnibus (GEO), 524 Genetic mutation, 734 Genetic polymorphisms, 478e479 Gestational diabetes, RAS in, 201e203 Gestational diabetes mellitus (GDM), 180 Glaucoma, 429e431 Glial cells, 755 AT1R and AT2R role in, 455e459 Glial fibrillary acidic protein (GFAP), 718e719 Global Burden of Disease (GBD), 42 Glomerular filtration, 701, 703e704 barrier, 158 Glomerular filtration rate (GFR), 186 Glomerular hydrostatic pressure, 701 Glomerulosclerosis, 235, 399e401 Glomerulus, RAAS in, 152e155 Glucocorticoids, 364 Glucose metabolism Ang (1e7), 652e653 Angiotensin II, 648 Glucose transporter (GLUT), 119e121, 648 GLUT2, 691 Glutamate, 452 receptor, 718 Glutamate transporter (1GLT-1), 452 Glutamate-aspartate transporter (GLAST), 452 Glutamatergic synapse, 719 Glutamatergic systems, 718 Glutamineeglutamate, 718e719 Glycerol phosphate dehydrogenase (GPDH), 645

785

786

Index

Glycogen synthase kinase 3 beta (GSK-3b), 653, 758 Glycolysis stress, 342 a-glycoprotein, 153e154, 425 Glycyrrhizic acid, 293e294 Gonadotropin-releasing hormoneebased drugs, 567 gp91phox subunit, 157e158 Granulocyte colony-stimulating factor (GCSF), 159e160 Growth factor, 244 Guinea pig ileum, 684e685 Gut motility, 682e688 esophagus, lower esophageal sphincter, and stomach, 683e684 large intestine, 686e688 small intestine, 684e686 Gut mucosal epithelial barrier, 672

H Haplotype-tagging single nucleotide polymorphism (htSNP), 31e32 Head, eyes, ears, nose and throat (HEENT), 435 Healthy animals, 2 Heart, 342e343 Heart failure (HF), 1, 275, 323, 389 actions of angiotensin II within spinal cord, 8e11 brain renineangiotensin in cardiovascular regulation in, 38e40 HF results in increase in resting levels of SNA, 2e3 consequence of increased SNA during HF, 2e3 role of angiotensin II, 3e8 circulating levels of angiotensin II in HF, 3 role of paraventricular nucleus of hypothalamus in HF, 7 Heart Outcomes Prevention Evaluation (HOPE), 276 Heat shock protein 70 kDa (Hsp70), 248e249 Hek293 cells, 737 Helicobacter pylori, 528 HELLP syndrome, 194 Hematopoiesis bone marrow renineangiotensin system in, 215e216 Hematopoietic bone marrow renin-angiotensin system local bone marrow renineangiotensin system in atherosclerosis, 217e219 and COVID-19 syndrome, 220e222 in hematopoiesis, 215e216 in hypertension, 219e220 in neoplastic hematopoiesis, 216e217

Hematopoietic RAS, 221e222 Hematopoietic stem cells, 216e217 Heparin, 362e363 Heparin cofactor II (HCII), 362e363 Heparin-binding EGF-like growth factor (HB-EGF), 241 Hepatitis Bvirus (HBV), 523e524 Hepatitis C virus (HCV), 523e524 Hepatocellular carcinoma (HCC), 512, 523e525 Heptapeptide hormone, 567, 574 Herpes virus infection (HIV), 603 Heterogeneity model, 457 High blood pressure, 317 High fat (HF), 645 High-molecular-weight kininogens, 380e381 Hindbrain regions, 717 Homeostatic processes, 699 Hormone serelaxin, 251 Hormone-sensitive lipase, 650 House dust mites (HDM), 289 Human ACE2 overexpression, 498 in coronavirus infection models, 497e498 in mouse brain, 496 in mouse heart, 497 in mouse podocytes, 497 in mouse/coronavirus infection models, 497e498 in rat vascular smooth muscle, 497 Human AGT (hAGT), 194e196 Human antigen R (HuR), 293 Human diseases, evidence in, 89e92 Human esophageal mucosa, 689 Human estrogen receptor-positive (HER2), 577 Human eye’s anatomy and physiology, 421e423 aqueous humor homeostasis and intraocular pressure, 423 ocular barriers, 422 ocuzlar blood flow regulation, 422e423 primary layers, 421 visual processing, 421 Human heart failure, 389 Human lung cancer cells, 574e575 Human pregnancy angiotensins in pathophysiology of, 179e180 circulating renineangiotensinealdosterone system in normal pregnancy, 185e187 changes in components of RAAS in human pregnancy, 185e187 intrarenal RAS in pregnancy, 187e190 intrauterine renineangiotensin system, 190e194 RAS and hypertension in pregnancy, 194e198 RAS in gestational diabetes, 201e203

Index

renineangiotensin system, 180e185 role of RAS in regulating fetal growth, 198e201 Human renin (hREN), 194e196 Humans, lentivirus-mediated ACE2 overexpression in fetal lung-1 (HFL-1), 291 6-hydroxydopamine (OHDA), 549, 719 5-hydroxyindoleacetic acid (5-HIAA), 551e552 Hydroxypropyl-b-cyclodextrins (HPbCD), 121, 553 Hyperalgesic responses, 602 Hypercholesterolemic mice, 645e647 Hyperdynamic circulation, 700 Hyperdynamic sepsis, 700e701 Hyperglycemia, 201, 235e236 Hyperplasia, 159e160, 643e644 Hypertensin, 699 Hypertension, 263, 272, 376e380, 550, 597, 734, 754e755 angiotensin II increases bloodebrain barrier disruption in, 377 brain renineangiotensin system in cardiovascular regulation in, 33e38 diseases, 452e453 drugs for, 318e324 local bone marrow renineangiotensin system in, 219e220 RAS and hypertension in pregnancy, 194e198 Hypertensive response sensitization (HTRS), 556 Hypertensive vascular disease, 319 Hyperthyroidism, 612 Hypertrophy, 643e644 Hypothalamicepituitaryeadrenal (HPA), 626e628 Hypothalamus in HF, role of paraventricular nucleus of, 7 Hypoxia, 704 Hypoxia inducible factor (HIF-1), 434 Hypoxia-inducible factor 1a (HIF-1a), 248, 273, 288e289, 574e575

I Idiopathic pulmonary fibrosis (IPF), 291 IL-1 receptor agonist (IL-1Ra), 250 Immune cells, 158e159, 214 Immuno histochemical analysis (IHC analysis), 578e579 Immunocytochemical techniques, 546 In vitro studies, 573e576 Inducible nitric oxide synthase (iNOS), 43e45, 529, 657

Inflammation, 134e136, 572. See also Neuroinflammation ACE2 role in, 85e86 Ang (1e7), 652 angiotensin II, 647e648 type 1 receptor role in, 82 type 2 receptors role in, 83e84 angiotensin-(1e7) and mas receptor role in, 86e87 angiotensin-converting enzyme role in, 80 inflammation-related phenotypes, 495 renin role in, 79 Inflammatory bowel disease (IBD), 399e401, 669 , 672, 688 local renineangiotensin system in intestine, 671e672 renineangiotensin system, 669e671 RAS cascade and biological effects, 670f renineangiotensin system and, 672e674 Inflammatory cells, 219, 246, 268, 287 Inflammatory diseases, 80 Inflammatory pain, 605e606 Inflammatory processes, 548e549 Inhaled corticosteroids (ICSs), 289e290 Innate chronic immune system, 378 Innate immune system, 378e380 Inositol 1, 4, 5-trisphosphate (IP3), 82 Insertion/deletion polymorphisms (I/D polymorphisms), 528 Insulin receptor aminopeptidase (IRAP), 107 Insulin resistance, 652 Insulin-like growth factor-1 (IGF-1), 270, 434 Insulin-regulated aminopeptidase (IRAP), 24e25, 109, 242, 598, 656, 682, 752 Intensive care units (ICU), 700 Intercellular adhesion molecule 1 (ICAM-1), 43e45 Interferon gamma (IFN-g), 43e45 Interferon-stimulated gene (ISG), 287 Interleukin 10 (IL-10), 36e37 Interleukin 6 (IL-6), 43e45, 643e644 Interleukin-1 (IL-1), 264e265, 356e357 Interleukin-1b (IL-1b), 554, 643e644 Intermediolateral cell (IML cell), 25e26, 375 Interstitial cells of Cajal (ICCs), 682 Intestinal epithelium, 688e689 Intestinal homeostasis, 682 Intestinal muscle contraction, 672 Intestine, local renineangiotensin system in, 671e672 Intracellular brain RAS, 343e344 Intracellular RAS, 335e336

787

788

Index

Intracellular renineangiotensin system brain, 343e344 heart, 342e343 intracellular RAS ligands, 344e348 kidney, 336e342 Intracerebroventricular (ICV), 4, 28, 32 administration, 553 infusion, 550e551 injection, 628 Intracrine functions, 77 Intraocular pressure (IOP), 423 Intrarenal perfusion in sepsis, 703e704 Intrarenal RAS (iRAS), 187e188 in pregnancy, 187e190 Intrarenal renineangiotensin system, 235e238 classical actions of ANG II in kidney, 237e238 Intrauterine renineangiotensin system, 190e194 RAS components in decidua in normal pregnancy, 193e194 RAS components in intrauterine membranes in normal pregnancy, 192e193 RAS components in placenta in normal pregnancy, 190e192 IR substrate (IRS), 648 Ischemia Management With Accupril Post-Bypass Graft via Inhibition of Converting Enzyme (IMAGINE), 276 Ischemic injury, 166 Ischemic kidneys, 597 Ischemic renovascular disease, 164e166 angiotensin II in ischemia nephropathy, 165e166 pathophysiology, 165 Ischemic reperfusion renal injury (IRI), 168e169 Isoproterenol-stimulated lipolysis, 650

J Jejunal glucose, 691e692 Juxtaglomerular cells (JG cells), 21e22, 79, 153e154, 355e356, 750e752

K Kallikrein, 382e383 Kallikreinekinin system (KKS), 380, 425e427 Ketamine, 718 astrocytes in ketamine-induced dopamineeglutamate imbalance model, 720e721 long-lasting effects, 718 Kidneys, 21e22, 151e152, 182, 336e342, 356e357 classical actions of ANG II in, 237e238 disease, 86

epithelial cells, 737 fibrosis, 246 injury, 481 system, 29e30 tissue, 395 Kininases, 380e381 Klotho, 250 Knockout (KO), 165e166 Kru¨ppel-like factor 15 (KLF15), 250e251 Kynurenic acid circle, 718e719

L Large intestine, 686e688, 692 Large tumor suppressor kinase (LATS), 737 Learning, 756e759 cognitive impairment and dementia, 758e759 memory and, 756e758 Left ventricular hypertrophy, 275, 741 Leukemic blast cells, 215e216 Leukocytes, 81, 272 Lewis Polycystic Kidney model (LPK model), 734e735 Ligands angiotensin II, 451 Limb ischemiare perfusion (LIR), 293 Limbic system, 754e755 Lipid droplets, 643 Lipid metabolism, 263 Lipid storage Ang (1e7), 650e651 Angiotensin II, 645 Lipolysis, 645 Lipopolysaccharide (LPS), 451 Lipoprotein receptor 1 (LRP-1), 347e348 Liposomes, 121 Liver fibrosis, 493 Liver metastasis, 577e578 Liver tissue, 394 Local bone marrow renineangiotensin system in atherosclerosis, 217e219 and COVID-19 syndrome, 220e222 in hematopoiesis, 215e216 in hypertension, 219e220 in neoplastic hematopoiesis, 216e217 Local renineangiotensin system in eye, 428e429 eye diseases and, 429e436 AMD, 432e433 DM, 431e432 glaucoma, 429e431 ocular SRA and COVID-19, 434e436 ROP, 433e434 in intestine, 671e672

Index

Locomotor sensitization, 720 Long-lasting ketamine effects in dorsal striatum, study of AT1-R involvement in, 722e726 Long-term depression (LTD), 756 Long-term potentiation (LTP), 756 Losartan carboxylic acid (LCA), 136e137 Low-molecular-weight heparin (LMWH), 363 Low-molecular-weight kininogens, 380e381 Lower esophageal sphincter (LES), 683e684 Luminal microbiota invasion, 672 Luminal obstruction-dependent renal arterial diameter, 161e162 Lung adenocarcinoma (LUAD), 291e292 Lung cancer, 526e527 ACE2 and, 291e292 cell, 575e576 Lung epithelial cells, 477e478 Lung fibrosis, 290e291 Lung involvement, 473, 479e480 Lung repair, role of ACE2 in, 296e297 Lung squamous carcinoma (LUSC), 291e292 Lymphatic vessels, 423 15-lypoxygenase, 268e269 Lys-des-Arg9-BK, 380e381 Lysosomes, 344e345

M Macrophage colony-stimulating factor (M-CSF), 43e45 Macrophages, 268 Magnetic resonance coil, 703 Magnetic resonance spectroscopy, 703 Major depressive disorder (MDD), 551 Malondialdehyde (MDA), 292e293 Mannose-6-phosphate receptor (M6P-R), 243 Marrow mesenchymal stem cells (MSCs), 288e289 Mas receptors (MasR), 25, 86, 107, 340, 342e343, 450, 683, 752 agonists, 113e122 angiotensin-(1e7) and mas receptor role in inflammation, 86e87 axis, 625, 628e629 Mas1 axisdtarget for cancer drug development, 570e573 Mas1 receptor axis, 567e570 biological processes mitigated by, 569f enzymatic synthesis and catabolism of, 568f pathway in control of proinflammatory reactive gliosis, 459e460 potentiating opposing function of, 324

Mas-related G proteinecoupled receptor (MrgD), 87e88, 109, 427e428, 598, 614, 644, 752 Maternal cardiovascular system, 185 Maternal circulating RAAS in pregnancies associated with FGR, 198e200 Matrix metalloproteinase-2 (MMP-2), 752e753 Matrix metalloproteinase-9 (MMP-9), 756 Mean arterial pressure (MAP), 700, 707 Mechanical vascular injury, 272 Median preopticarea (MnPO), 24 Membrane protein (M protein), 474 Membrane-spanning regions, 682 Memory, 756e759 cognitive impairment and dementia, 758e759 and learning, 756e758 Menon Cancer Research 2007, 576e577 Menstrual cycle, 185e186 Mertyrosine kinase (MerTK), 43e45 Mesangium, 157e158 Mesenchymal stem cells, 645e647 Mesenchymal-derived stem cells (MDSCs), 608 Messenger RNA (mRNA), 478 Metabolic associated fatty liver disease (MAFLD), 642 Metabolic syndrome model, 653 renineangiotension system in, 41e42 Metabolism, 643 Metalloproteinases (MMP), 24 Metastatic colorectal cancer (mCRC), 529 Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), 719 1-methyl-4-phenylpyridinium (MPP), 454 Microalbuminuria, 740 Microglia, 379, 449e450, 455e456 MicroRNAs (miRNAs), 521 Middle cerebral artery occlusion (MCAO), 553, 755e756 Midkine, 271, 274 Midregional proadrenomedullin (MR-proADM), 275 Mineralocorticoid receptor (MR), 248e249, 323, 360e361 Mineralocorticoid receptor antagonists (MRA), 46 Mitochondria, 648e650 Mitochondrial assembly receptors (MASRs), 512, 522e523 Mitochondrial dysfunction, 112, 705e706 Mitochondrial expression of ACE2, 344 Mitochondrial reactive oxygen species, 270e271 Mitogen-activated kinase (MAP), 238e240

789

790

Index

Mitogen-activated protein kinases (MAPKs), 24, 124e125, 182, 267, 648e650, 757 Mitosis, 598 Modified PTSD Symptom Scale (M-PSS), 630e631 Molecular biology, 681 Molecular pathway, 736 Monocarboxylate transporters (MCTs), 451e452 Monoclonal antibodies (mAb), 319, 323 Monocrotaline (MCT), 287e288 Monocyte chemoattractant protein-1 (MCP-1), 43e45, 82, 85, 245, 271, 336e340, 647e648 Monocyte chemotactic protein-induced protein (MCPIP1), 43e45 Monotherapy, 583 Mood disorders, 551 ACE2/Ang-(1e7)/mas receptors role in, 551e552 Morris water maze, 495 Mouse brain, 496 Mouse heart, 497 Mouse podocytes, 497 Mucosal blood flow, 689 Mucosal function, 684e685 Mucosal inflammation, 669 Multihormone system, 749 Multiorgan dysfunction, 700 Multiplex probe amplification (MPA), 524e525 Muscle hypertrophy, 159e160 Muscle pain, 608e609 Muscle sympathetic nerve activity (MSNA), 25 Myalgic encephalomyelitis (ME), 609 Mycobacterium ulcerans, 603e604 Mycolactone, 603e604 Myeloid cells, 214 Myeloid differentiation factor 2 (MD2), 245 Myeloid migratory cells, 214 Myocardial infarction, 42e43 renineangiotensin system in, 45e46 pathogenesis of, 42e46 Myocardial tissue, 42 Myofibroblasts, 246 Myometrium, 179e180 Myosin light chain (MLC), 673e674

N N-acetylcysteine, 241 N-aminoimidazolidin-2-one, 119 N-methyl glycine, 126e127 N-methyl-D-aspartate receptor (NMDA receptor), 756

N-terminal signal peptide, 392 NADPH oxidase (Nox), 157e158, 296e297, 336e340, 513e514 NOX2, 112 Nox4, 580e581 Nasopharyngeal carcinoma, 579 Natriuretic peptide receptor-A (NPR-A), 364 Neoplastic hematopoiesis, local bone marrow renineangiotensin system in, 216e217 Neovascularization, 524 Nephrin, 158 Nephron, 169 Nephronophthisis (NPHP), 733, 737 Nephrotic syndrome (NS), 89 Neprilysin (NEP), 182, 382e383, 427 Nerve dysfunctions, 614 Nerve growth factor (NGF), 604, 757 Nervous system, 480e481 Neupogen, 580 Neural network, 29 Neuroactive angiotensin peptides, 749 Neurodegeneration, 112, 719 Neurodegenerative diseases, 452e453 ACE2/Ang-(1e7)/mas receptors role in, 547e551 processes, 754 Neuroendocrine functions, 546e547 Neurogenic manifestations, 606e607 Neurohumoral systems, 1 Neuroinflammation, 112, 378e380 dichotomy in, 455e459 diseases, 452e453 neuroinflammation-related mental disorders, 720e721 Neuroinflammatory processes, 722 Neuroinflammatory responses, 601 Neuromodulatory molecules, 749 Neuropathic pain, 600, 603e605 Neuroplasticity, 757 Neuroprotective effects, 548e549, 721 Neuropsychiatric disorders, 625e626 Neuroreticular complex, 219e220 Neurotransmission systems functioning, 718e719 Neurovascular coupling, 753 orchestrating, 718e719 Neurovascular structure and function, regulation of, 752e754 Neutral amino acid, 491e492 transporter, 691 Neutral endopeptidase (NEP), 84, 380e381, 597e598 Neutrophil infiltration, 689

Index

Nicotinamide adenine dinucleotide phosphate (NADPH), 194e196 Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), 24 Nitric oxide (NO), 108e109, 156, 263, 335, 340, 453, 480, 608, 683, 691 Nitrogen monooxide (NO), 237 NO synthase (NOS), 340 Nociceptive system, 601 Nociceptors, 601 Nocifensive pain, 602 Nonalcoholic steatohepatitis (NASH), 523e524 Nonesmall-cell lung cancer (NSCLC), 291, 512 Norepinephrine, 219e220 release, 2 spillover, 2 Normal glucose tolerance (NGT), 202 Normal pregnancy. See also Pregnancy circulating renineangiotensinealdosterone system in, 185e187 RAS components in decidua in, 193e194 RAS components in intrauterine membranes in, 192e193 RAS components in placenta in, 190e192 NOS3 protein, 340 Nuclear factor kappa B (NF-kB), 43e45, 82, 266e267, 363, 451, 528, 647 Nuclear factor of activated T cells (NFAT), 359e360 Nucleocapsid protein (N protein), 474 Nucleus of tractus solitarius (NTS), 24, 375 Nutrient absorption, 691

O Obesity, 272, 493, 642 additional angiotensins, 654e658 alamandine, 657 Ang III or Ang (2e8), 654e656 Ang IV or Ang (3e8), 656e657 Ang (1e7), 650e654 adipogenesis, 652 browning, 653e654 glucose metabolism, 652e653 inflammation, 652 lipid storage, 650e651 main functions in wat, 644e650 adipogenesis, 645e647 browning, 648e650 glucose metabolism, 648 inflammation, 647e648 lipid storage, 645 Obesity-induced WAT dysfunction, 648

Occlusive renovascular diseases, 155e156 Ocular barriers, 422 Ocular blood flow regulation, 422e423 Ocular SRA, 434e436 Oligodendrocyte precursor cells (OPC), 453 Open-angle glaucoma, 429 Oral mucosa, 393e394 Organum vasculosum of lamina terminalis (OVLT), 4, 8, 24 Osmotic minipumps, 576e577 Osteoclastogenesis, 579 Osteoclasts, 578e579 Osteopontin, 162e163, 165e166 KO, 165e166 Ovalbumin (OVA), 289 Ovarian cancer, 523 Overall survival (OS), 522 Ovine kidney, 345e347 Oxidative stress, 112, 160, 165, 269, 342, 720, 722 Oxygen consumption, 157e158 Oxygenation in sepsis, 703e704

P p38 mitogen-activated protein kinase (p38 MAPK), 43e45 Paclitaxel (PCX), 607 Pain basics on, 600e601 COVID-19, RAS, thyroid status, and, 613e615 link between RAS, thyroid hormones, and, 610e612 renineangiotensin system, 597e600 role of angiotensin and major receptors in, 602e610 angiotensin and cancer pain, 606e608 angiotensin and fibromyalgia, 609e610 angiotensin and inflammatory pain, 605e606 angiotensin and muscle pain, 608e609 angiotensin and neuropathic pain, 603e605 angiotensin and sickle celleassociated pain, 610 angiotensin in nocifensive pain, 602 roles of angiotensin in context of, 601e602 Pancreas tissue, 397 Pancreatic cancer, 512, 526 Paraaortic splanchnopleura (P-Sp), 213 Parabrachial nucleus (PBN), 24 Paracrine functions, 77, 181, 213, 681 Paraventricular nucleus (PVN), 4, 23, 375, 455e456, 625e626, 754e755 role of paraventricular nucleus of hypothalamus in HF, 7

791

792

Index

Parenchyma, 734 Parkinson’s disease (PD), 110, 457, 547e549, 718e719 Particulate matter (PM), 291 Pathogen-associated molecular pattern (PAMP), 453 Pathogenesis, 754 Pathological pain, 598e599 Pathological processes, 705e706 Pathophysiological factors, 700 Pathophysiological mechanisms, 552 pck rodent model, 739 PCX-associated acute pain syndrome (P-APS), 607 PCX-induced neuropathic pain (PINP), 607e608 Penumbra, 755 Pepstatin, 137e138 Peptides, 117e119, 266e267, 597 hormones, 567 Peptidomimetic saralasin and sarile, 126e127 Periaqueductal gray (PAG), 605 Perindopril and Remodeling in Elderly with Acute Myocardial infarction (PREAMI), 276 Peripheral neuropathy, 603 Peristalsis, 682 Peroxisome proliferatoreactivated receptor a (PPARa), 752e753 Peroxisome proliferatoreactivated receptor g (PPARg), 645e647 Pharmacodynamic properties, 567 Pharmacological blockade, 735e736 Pharmacological drugs, 669e670 Pharmacological investigations, 689 Pharmacological treatments, 718e719 Phorbol-12 myristate 13-acetate (PMA), 336e340 Phosphatidylinositol 3-kinase (PI3K), 240, 336e340, 652 Phospholipase A2 (PLA2), 24 Phospholipase C (PLC), 24, 240, 683 Phospholipase D, 24 Photoreceptors, 421 Physiological functions, 717, 733 Physiological reaction, 600 Placenta, 179e180, 190e194 Placental growth factor (PLGF), 293e294, 574e575 Placental RAS expression in pregnancies associated with FGR, 200e201 fetal sex, gestation, and labor on expression of, 192 Planar cell polarity (PCP), 736e737

Plasma kallikrein, 382e383 Plasma rennin activity (PRA), 198e199 Plasma superoxide dismutase-2 (PSD-2), 287e288 Plasminogen activator inhibitor 2 (PAI-2), 269 Plasminogen activator inhibitor-1 (PAI-1), 242, 247e248, 269, 656 Plasticity of adipose tissue, 643 Platelet-derived growth factor (PDGF), 270, 570 Polycystic kidney and hepatic disease 1 (PKHD1), 733 Polycystic kidney disease (PKD), 733 ACE inhibitors/ARB in clinical trials, 739e741 Ang II cross-talk with cystogenic pathways, 736e737, 738f Ang II in abnormal water and salt handling in, 738e739 Ang II in extrarenal disease in, 739 evidence of RAS dysregulation in, 734e736 Polycystin-1 (PC-1), 733 Polycystin-2 (PC-2), 733 Polyethylene glycol (PEG), 121 Polyketide toxin, 603e604 Polymerase chain reaction analysis, 80 Polymorphisms, 243 Postmortem analysis, 719 Postmortem study, 549 Postoperative hypotension, angiotensin II treatment for, 711e712 Postoperative vasoplegia, 711e712 Posttraumatic stress disorder (PTSD), 623, 630 Potassium-sparing diuretic, 360e361 PR-domain containing 16 (PRDM16), 648e650 Preclinical research, 573e581 Ang-(1e7)dcombination therapy, 580e581 animal models, 576e579 in vitro studies, 573e576 Preeclampsia, 194 Prefrontal cortex (PFC), 720 Pregnancy intrarenal RAS in, 187e190 for mammals, 180 pregnancy-specific organ, 179e180 RAS and hypertension in, 194e198 Pregnant endometrium, 193 Preterm premature rupture of membranes (PPROMs), 193e194 Prevention of Events with ACE inhibition (PEACE), 276 Primary hypertension, 324 Primary open-angle glaucoma, 429e430 Primary sclerosing cholangitis (PSC), 399e401

Index

Pro-fibrotic processes, 545e546 Profibrotic proteins, 737 Programmed death ligand 1 (PD-L1), 581 Progression-free survival (PFS), 529 Proheparin-binding EGF (HB-EGF), 241 Proinflammatory cytokines (PICs), 250, 379, 554, 643e644, 674 Proinflammatory markers, 652 Proinflammatory reactive gliosis, angiotensin (1e7)/MasR pathway in control of, 459e460 Proliferating nuclear antigen (PCNA), 248 Proliferation, 573e574 Prolyl carboxypeptidase (PRCP), 84 Prolyl endopeptidase (PEP), 84 Prolyl hydroxylase (PHD), 248 Prolyl-4-hydroxylase (P4H), 290e291 Prophylactic treatment, 580 Prorenin, 153e154, 182, 425 Prorenin receptor (PRR), 34, 79, 109, 182, 243, 508, 670e671, 750e752 Prostate cancer, 521e522 Proteases, 165 Protein C inhibitor (PCI), 362e363 Protein kinase, 574 Protein kinase A (PKA), 188e190, 568e569 Protein kinase B (pKB), 575 Protein kinase C (PKC), 82, 188e190, 243e244, 336e340, 431e432 Protein kinase Ca (PKCa), 757 Proteins, 355 Proteinuria, 235e236, 246e247 Proteolytic activation, 670e671 Proton pump inhibitors (PPIs), 196 Proximal tubular AGT, 187 Proximal tubules, 345e347 Psychiatric illness, 642 Psychological stress, 623 Psychostimulant effects, 720 Pulmonary alveoli, 396e397 Pulmonary arterial hypertension (PAH), 288e289 Pulmonary arterial-SMCs (PA-SMCs), 287e288 Pulmonary fibrosis, ACE2 and, 290e291 Pulmonary hypertension (PH), 85, 287e289, 495 Pulmonary microvascular-ECs (PMV-ECs), 293 Pulse-wave velocity (PWV), 739

Q Quinapril Ischemic Event Trial (QUIET), 276

R Randomized controlled trials (RCTs), 363

Rat renal tissue, 344e345 Rat transgenic model, 32 Rat vascular smooth muscle, 497 Reactive astrocytes, angiotensinogen expression in, 454 Reactive astrogliosis generic response to brain injury, 453e454 Reactive gliosis, 453 Reactive oxygen species (ROS), 43e45, 86, 112, 119e121, 184, 241, 264e265, 292e293, 336e340, 380, 513e514, 734e735 Receptor binding domain (RBD), 392 Receptor Mas (MasR), 267 Receptor relaxin family peptide receptor 1 (RXFP1), 251 Receptor-binding domain (RBD), 363, 476 Recombinant human ACE2 (rhACE2), 324 Reducing uterine perfusion pressure (RUPP model), 194e196 Regeneration, role of ACE2 in, 296e297 Renal artery pressure, 161e162 Renal bioenergetics, 703 Renal blood flow (RBF), 152e153, 161e162, 164e165, 702 Renal cells, 235, 249 Renal diseases, 235 Renal dysfunction, 151e152 Renal fibrogenesis angiotensin II as mediator of intrarenal renineangiotensin system, 235e238 renal renineangiotensin system, 238e251 Renal fibrosis, 246 ANG II and, 246e251 Renal functions, 681, 741 Renal growth, ANG II and, 243e244 Renal hemodynamic actions, 152e153 Renal inflammation, ANG II and, 245e246 Renal medulla, 703e704 Renal mitochondria, 345e347 Renal norepinephrine spillover, 2 Renal organogenesis, 244 Renal renineangiotensin system, 238e251 ANG II and renal fibrosis, 246e251 ANG II and renal growth, 243e244 ANG II and renal inflammation, 245e246 Renal replacement therapy, 707 Renal sympathetic nerve activity (RSNA), 41 Renal tubular cells, 250 Renal tubules, 151e152 Renal vascular bed, 702 Renal vascular resistances (RVR), 738e739 Renal vasodilatation, 701

793

794

Index

Renin, 79, 109, 182, 214, 319e324, 355e356 angiotensinogen, 320e323 blocking activity of ACE/Ang II/AT1-R, 323e324 cells, 216e217 inhibitors, 137e138 peptides, 28 potentiating opposing function of ACE2/Ang(1e7) /Mas-R axis, 324 promoter, 23 role in inflammation, 79 transgenic rats, 34 Renineangiotensin system (RAS), 21, 77, 107, 180e185, 213, 235, 265e266, 285e286, 318, 335, 375, 389e391, 419, 423e428, 449, 473, 491e492, 507e508, 545e546, 567e568, 597e600, 610e615, 623e626, 669e671, 681, 699, 717, 733 angiotensin (1e7) and Mas1, 512 angiotensin and types, 512 angiotensin I, 512 angiotensin II, 512 angiotensin-converting enzyme 2, 512 angiotensinogen, 512 astrocytes essential homeostatic cells in CNS respond to brain RAS activation, 451e453 and atherosclerotic plaque, 42e45 bioactive peptides, 686e687 in brain, 109e112 and brain renineangiotensin system, 449e451 bypass loops for RAS activation in cancer, 513 classic renineangiotensin system axis, 79e84 angiotensin II, 80e84 angiotensin-converting enzyme, 80 renin, 79 clinical evidence, 629e632 components as therapeutical targets for stressassociated conditions, 626e629 activation of ACE2/angiotensin- (1e7) /mas receptor axis, 628e629 blockade of classical axis, 626e628 components as therapeutical targets for stressassociated conditions, 626e629 activation of ACE2/angiotensin-(1e7)/mas receptor axis, 628e629 blockade of classical axis, 626e628 components in decidua in normal pregnancy, 193e194 fetal sex, gestation, and labor on expression of RAS in fetal membranes, 193e194 components in intrauterine membranes in normal pregnancy, 192e193

gestation and labor on expression of RAS in fetal membranes, 193 components in placenta in normal pregnancy, 190e192 fetal sex, gestation, and labor on expression of placental RAS, 192 contemporary renineangiotensin system, 624e625 counter regulatory renineangiotensin system axis, 84e87 angiotensin-(1e7), 85e86 angiotensin-converting enzyme 2, 84e86 mas receptor, 86 and epithelial functions, 688e692 esophagus and stomach, 689e690 large intestine, 692 small intestine, 690e692 evidence in human diseases, 89e92 evidence of RAS dysregulation in PKD, 734e736 in gastrointestinal functions, 681 in gestational diabetes, 201e203 and gut motility, 682e688 esophagus, lower esophageal sphincter, and stomach, 683e684 large intestine, 686e688 small intestine, 684e686 and hypertension in pregnancy, 194e198 and inflammatory bowel disease, 672e674 inhibition of, 530 intracellular RAS ligands, 344e348 mediators, 87e89 alamandine, 87e88 Ang-(1e9), 88e89 in myocardial infarction, 45e46 new therapeutic strategies, 623e624 organization, 21e25 in pathogenesis of myocardial infarction, 42e46 primary components of RASeangiotensin pathway, 508e513 RAS-derived peptides, 450 rennin, 513 role of RAS in regulating fetal growth, 198e201 in stress, depression, and COVID-19, 31e33 vascular effects to behavioral modulation, 625e626 Renineangiotensin system inhibitor (RASi), 524e525 Renineangiotensinealdosterone system (RAAS), 1, 151e152, 317e318, 355, 390, 419, 508e514, 749 cascade, 390e391 two axes of, 402

Index

changes in components of RAAS in human pregnancy, 185e187 components of, 762 in glomerulus and tubular region, 152e155, 180 modulation of RAAS as therapy for cognitive impairment and dementia, 759e762 ACE inhibitors, 759e760 ACE2/angiotensin /MasR axis, 761 angiotensin IV and AT4R agonist, 761e762 AT1R antagonists, 760 AT2R agonists, 760e761 components of RAAS, 762 in normal pregnancy, 185e187 physiology of, 355e356 primary components of RASeangiotensin pathway, 508e513 angiotensin (1e7) and Mas1, 512 angiotensin and types, 512 angiotensin-converting enzyme 2, 512 angiotensinogen, 512 bypass loops for RAS activation in cancer, 513 rennin, 513 RAS components and cancer, 513e514 and SARS-CoV-2, 356e357 therapeutic venues in context of SARS-CoV-2 infection, 358e364 Rennin, 513, 712e713 Renovascular diseases, angiotensin in ARVD, 161e164 diabetic nephropathy, 167e169 ischemic renovascular disease, 164e166 RAAS in glomerulus and tubular region, 152e155 renovascular hypertension, 155e161 Renovascular hypertension (RVH), 155e161 AT2 receptor activation in, 160e161 pathophysiology of, 156e158 role of angiotensin II in, 158e160 Reproductive system, 598e599 Respiratory system, 479e480 Response Evaluation Criteria In Solid Tumors (RECIST), 582e583 Restless legs syndrome, 631 Retinal cells, 347e348 Retinal endothelial cells, 422 Retinopathy of prematurity (ROP), 429, 433e434 Reverse transcriptaseepolymerase chain reaction (RT-PCR), 521 RNA interference (RNAi), 320 Rostral ventral lateral medulla (RVLM), 4, 6, 23, 121, 375, 754e755 actions of angiotensin II within, 7e8

S Salivary gland, 398e399 Salt absorption, 672 Salt balance, 335 Salt handling in PKD, Ang II in abnormal water and, 738e739 Sarlasarin, 133e134 Schizophrenia, 720 resembling, 718 Secondary hypertension, 194 Secretory-transport processes, 684e685 Segmentation, 682 Selective serotonin reuptake inhibitors (SSRIs), 551e552 Senescence-accelerated mouse prone 8 (SAMP8), 550e551 Sensory neurons, 601 Sepsis, 700 angiotensin II, emerging vasopressor for use in, 707e711 intrarenal perfusion and oxygenation in, 703e704 model of, 700e701 Serine protease, 182 Serineprotease inhibitor (SERPIN), 512 Serineethreonine kinase, 671 Serious adverse event (SAE), 582 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 294e295, 389, 473e475, 492e493, 613, 629, 670e671 ACEIs/ARBs, 359e360 aldosterone inhibitors, 360e361 beta-blockers, 361e362 direct renin inhibitor, 358e359 downregulation of ACE2 after binding, 406 effects of SARS-CoV-2 infection, 479e481 cardiovascular system, 480 gastrointestinal system, 481 nervous system, 480e481 respiratory system, 479e480 urinary system, 481 glucocorticoids, 364 heparin, 362e363 renineangiotensinealdosterone system, 356e357 therapeutic venues in context of, 358e364 spike (S) protein of, 474e475 Short hairpin RNA (shRNA), 320 Sickle celleassociated pain, 610 Signal peptide (SP), 512 Signal transducer and activator transcription factor (STAT), 124e125, 266e267

795

796

Index

Single nucleotide polymorphisms (SNPs), 478, 630 Sirtuins (Sirt3), 160 Skeletal muscle pain, 611e612 Small for gestational age (SGA), 198 Small intestine, 684e686, 690e692 Small-cell lung cancer (SCLC), 291e292 Smooth muscle cells (SMCs), 287, 682 Sodium deficiency, 187 Sodium excretion unless tubuloglomerular balance, 187e188 Sodium hydrogen exchange transporter (NHE-3), 336e340, 672 Sodium intake, regulation of, 28e29 Sodium-dependent glucose transporter (SGLT-1), 119e121, 691 Sodiumevitamin C cotransporters (SVCT), 136e137 Soluble ACE2 (sACE2), 182e183, 221e222, 359e360, 492 Soluble endoglin (sEng), 196 Soluble guanylate cyclase (sGC), 340 Spike protein (S protein), 220e221, 474, 497 interaction between S protein and ACE2, 476e477 of SARS-CoV-2, 474e475 Spinal cord actions of angiotensin II within, 8e11 AT1R within, 8e9 changes in spinal cord AT1R during heart failure, 11 regulation of sympathetic nerve activity by AT1R within, 9e11 Spironolactone, 360e361 Spontaneous hypertension (SHR), 48 Spontaneous hypertensive rats (SHR), 321, 379, 455e456, 546e547 Spontaneously hypertensive stroke-prone rat (SHRSP), 497 Src-homology phosphatise, 673 Statins, 347e348 Stem cells, 190e192 Stomach, 683e684 Streptozotocin-induced allodynia, 605 Streptozotocin-induced diabetes mellitus, 692 Streptozotocin-induced diabetic rats (STZ-DI), 41 Stress, 31e32 behaviours, 628 Stroke, 755e756

Stroke-prone spontaneously hypertensive (spSH), 555e556 Stromelysin 2 (ST2), 275 Subfornical organ (SFO), 4, 8, 23, 754e755 Supraoptic nucleus (SON), 23, 754e755 Sympathetic activation, 626e628 Sympathetic nerve activity (SNA), 1 blockade of central angiotensin type 1 receptor decreases, 4e6 consequence of increased SNA during HF, 2e3 HF results in increase in resting levels of, 2e3 Sympathetic nervous system, 1, 355e356, 493 Systemic endocrine cascade, 669 Systemic renineangiotensin system, cooperation of, 21e25 Systemic sclerosis (SSc), 289 Systemic syndrome, 161 Systolic Blood Pressure Intervention Trial (SPRINT), 317

T T lymphocytes, 529, 673 Tachycardia, 701e702 Tachykinins, 687e688 Targeting renineangiotensin system ACE inhibitors, 128e132 ACE2 activators, 123e125 AT1R blockers, 133e137 AT2R agonists, 125e127 drug development strategies, 113e122 renin inhibitors, 137e138 renineangiotensin system in brain, 109e112 Telmisartan, 134e136 Tenascin (TNC), 608 Tetrodotoxin (TTX), 683, 687 The Cancer Genome Atlas (TCGA), 524 Thyroid hormone response elements (TREs), 613e614 Thyroid hormones, 610e612 Thyroid status, 613e615 Time-intensive process, 124e125 Tissue factor plasminogen inhibitor (TFPI), 362e363 Tissue inhibitor of metalloproteinase (TIMP-1), 248 Tissues localization of ACE2 in, 393e399 kidney tissue, 395 liver tissue, 394

Index

pulmonary alveoli, 396e397 tissue in digestive system, 397e399 tissue-specific functions, 669 Tolerance, 163e164 Toll-like receptors (TLRs), 245, 380 within central nervous system, 380 TLR4, 40 Tongue mucosa, 398e399 Traditional cardiovascular risk factors, 263 Trans model, 457 Transcription factors (TFs), 291e292, 525 Transforming growth factor beta (TGF-b), 45, 87, 336e340, 524, 574, 737 mRNA expression, 572 Transforming growth factor-alpha (TGF-a), 241 Transgenic mice, 496 Transgenic rat model, 650e651 Transgenic rodent models with altered ACE2 expression, 494t Transient receptor potential 6 channels (TRPC6), 151e152 Transmembrane protease serine 2 (TMPRSS2), 33, 220e221, 295, 361, 435 Traumatic brain injury (TBI), 552e553, 556e557 Triglycerides synthesis, 645 2,4,6-trinitrobenzene sulfonic acid (TNBS), 673 1,4,5-trisphosphate (IP3), 683 Tropomyosin-related kinase receptor A (TrkA), 757 Trypsin, 182 Tubular region, RAAS in, 152e155 Tubules, 246 cells, 345e347 before injury, 165 b-tubulin expression, 603e604 Tubuloglomerular feedback (TGF), 151e152 Tumor angiogenesis, 571e572 Tumor growth factor-b (TGF-b), 273 Tumor microenvironment (TME), 513 Tumor necrosis factor (TNF), 554 Tumor necrosis factor alphaeconverting enzyme (TACE), 287 Tumor necrosis factor-a (TNF-a), 82, 264e265, 356e357, 607e608, 647 Tumor-associated macrophages (TAMs), 529 Two-kidney two-clip model, 156 Type II epithelial cells, 396e397

U Ulcerative colitis (UC), 672 Uncoupling protein 1 (UCP-1), 648e650 Unilateral ureteral obstruction (UUO), 245 Upper gastrointestinal tract, 683e684, 689e690 RAS effects on epithelial function in, 689f on motor function in esophagus and stomachs, 684f Urinary angiotensinogen, 734e735 Urinary system, 481

V Vascular cell adhesion molecule-1 (VCAM-1), 43e45, 572 Vascular cells, 152 Vascular contributions to cognitive impairment and dementia/high-fat diet (VCID/HF), 119e121 Vascular dementia (VaD), 758 Vascular effects to behavioral modulation, 625e626 Vascular endothelial growth factor (VEGF), 432, 521, 524, 553e554, 574e575 Vascular endothelium, 264, 360, 395 Vascular growth factor (VEGF), 273 Vascular smooth muscle cells (VSMCs), 43, 265, 268, 497, 568e569 Vascular system, 734 Vascular tunic, 421 Vasoconstrictor actions, 701 Vasoconstrictor drugs, 704 Vasoconstrictor effects, 700 Vasodilatory shock, 699, 707 Vasoplegia, 699 Vasopressin, 154 Vasopressin 2 receptor (V2R), 736 VEGF receptoretyrosine kinase inhibitor (VEGF-TKI), 581 Venous thromboembolic events, 699 Ventrolateral medulla (VLM), 24 Visceral WAT (vWAT), 643

W Water intake, regulation of, 28e29 Watereelectrolyte balance, brain renineangiotensin system in regulation of, 28e30

797

798

Index

White adipose tissue (WAT), 643, 645e647 Wild-type (WT), 165e166 Wnt signalling, 736e737 Wnt-induced secreted protein-1 (WISP1), 736e737 World Health Organization (WHO), 429, 473, 623, 642

X X chromosome, 286, 493

Xanthenone (XNT), 123, 629 Xenograft tumors, 578

Y Y-maze assays, 495

Z Zinc metallopeptidase, 286 Zinc-dependent monocarboxypeptidase, 123