The Protective Arm of the Renin Angiotensin System (RAS) - 1st Edition - ISBN: 9780128013649, 9780128014851

The Protective Arm of the Renin Angiotensin System (RAS)

1st Edition

Functional Aspects and Therapeutic Implications

Editors: Thomas Unger U. Muscha Steckelings Robson Souza dos Santos
eBook ISBN: 9780128014851
Paperback ISBN: 9780128013649
Imprint: Academic Press
Published Date: 22nd April 2015
Page Count: 316
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The Protective Arm of the Renin Angiotensin System: Functional Aspects and Therapeutic Implications is the first comprehensive publication to signal the protective role of a distinct part of the renin–angiotensin system (RAS), providing readers with early insight into a complex system which will become of major medical importance in the near future. Focusing on recent research, The Protective Arm of the Renin Angiotensin System presents a host of new experimental studies on specific components of the RAS, namely angiotensin AT2 receptors (AT2R), the angiotensin (1–7) peptide with its receptor Mas, and the enzyme ACE 2, which exert significant beneficial, health-promoting actions by counterbalancing the well-known harmful arm of the RAS with its classical angiotensin AT1 receptor. This innovative concept of the protective arm of the RAS, examined in this reference, represents an indispensable background and will be a strong support for biomedical students, researchers, cardiologists, surgeons, nephrologists, diabetologists, and endocrinologists, as well as any other physician or researcher concerned with RAS physiology, pathophysiology and clinical implications.

Key Features

  • Provides a complete understanding of the protective side of the Renin Angiotensin System (RAS) involving angiotensin AT2 receptor, ACE2, and Ang(1-7)/Mas receptor
  • Combines the knowledge of editors who pioneered research on the protective renin angiotensin system including; Dr. Thomas Unger, one of the founders of AT2 receptor research; Dr. Ulrike M. Steckelings, who contributed significantly to first preclinical studies with a novel specific AT2-agonist, and Dr. Robson Santos who pioneered research on angiotensin-(1-7) and its receptor Mas.
  • Shows that the protective RAS axes are able to ameliorate the course of several cardiovascular, renal, metabolic and neurological diseases
  • Provides the basis for the understanding of a novel therapeutic approach to stimulate components of the protective arm of the RAS.


Cardiology researchers, Cardiologists, Surgeons, Nephrologists, Diabetologists, and Endocrinologists

Table of Contents

  • Chapter 1: The Angiotensin AT2 Receptor: From Enigma to Therapeutic Target
    • Abstract
    • Introduction
  • Chapter 2: The AT2 Receptor: Historical Perspective
    • Abstract
    • Background to the Early Involvement of Ciba-Geigy in the Angiotensin Field
    • Two Ang II Receptor Subtypes
    • Angiotensin II Receptor Nomenclature
    • Early Research on the Role of the AT2 Receptor
    • Conclusion
  • Chapter 3: Animal Models with a Genetic Alteration of AT2 Expression
    • Abstract
    • Introduction
    • Blood Pressure
    • Cardiac Disease
    • Vascular Disease
    • Renal Disease
    • Neural Disease
    • Conclusion
  • Chapter 4: AT2 Receptor Signaling: Solved and Unsolved
    • Abstract
    • Introduction
    • AT2R Dimerization
    • Proliferation and Differentiation
    • Apoptosis
    • Inflammation
    • Fibrosis
    • Solved and Unsolved Issues
  • Chapter 5: AT1R–AT2R Cross Talk
    • Abstract
    • Cross Regulation of Angiotensin II Type 1 Receptor and the Angiotensin II Type 2 Receptor
    • Functional Significance of the AT1R–AT2R Cross Talk
    • Conclusion
  • Chapter 6: The Angiotensin AT2 Receptor in Myocardial Infarction
    • Abstract
    • Introduction
    • AT2 Receptor Expression in the Heart
    • Acute-Phase Postmyocardial Infarction
    • Late-Phase Postmyocardial Infarction
    • Conclusion
  • Chapter 7: AT2R, Vascular Effects, and Blood Pressure
    • Abstract
    • Acknowledgments
    • Introduction
    • AT2 Vasorelaxation: In Vitro Preclinical Studies
    • Acute AT2R Vasodilatation/BP Effects: In Vivo Preclinical Studies
    • Chronic AT2R Effects on BP: Preclinical Studies
    • Human Vascular AT2R Function: ex vivo and In Vivo Studies
    • AT2R Vasorelaxation: Why Is There no Translation into Antihypertensive Effects in Chronic Studies?
  • Chapter 8: AT2R in Nervous System
    • Abstract
    • Introduction
    • AT2R Expression in CNS
    • AT2R Expression in Neuronal Injury
    • AT2R-Mediated Effects in CNS Cells
    • AT2R in Peripheral Neuronal Injury
    • AT2R Stimulation in Stroke
    • AT2R in Spinal Cord Injury
    • AT2R in Multiple Sclerosis
    • AT2R in Traumatic Brain Injury
    • Conclusion
  • Chapter 9: Roles of AT2R in Cognitive Function
    • Abstract
    • Acknowledgments
    • Introduction
    • Preventive Effects of ARB on Cognitive Decline and Dementia
    • Protection Against Ischemic Brain Damage by AT2R Stimulation
    • Role of AT2R Stimulation in Cognitive Function
    • Role of AT2R-Associated Proteins in Cognitive Function
    • Conclusion
  • Chapter 10: The Protective Role of Angiotensin II (AT2) Receptors in Renal Disease: Molecular Mechanisms and Indications for AT2 Agonist Therapy
    • Abstract
    • Introduction
    • Renal AT2R Expression
    • Findings from AT2R Knockout (AT2KO) Mice
    • AT2R-Mediated Signaling Pathways
    • Renoprotective Mechanisms of AT2R Stimulation
    • AT2R in Renal Disease Associated with Obesity/Diabetes
    • Conclusion
  • Chapter 11: AT2 Receptors and Natriuresis
    • Abstract
    • Introduction
    • Renal Expression of AT2Rs
    • AT2R Induction of Natriuresis: Initial Evidence
    • Role of Angiotensin III in AT2R-Induced Natriuresis
    • Nephron Sites and Mechanisms of AT2R-Induced Natriuresis via ANG III
    • AT2R-Dopamine D1-Like Receptor Interactions
    • Physiological Significance of Renal AT2Rs in Renal Na+ Excretion
    • AT2R-Induced Natriuresis in Disease States
    • AT2R Agonist Administration and Natriuresis
    • Conclusion
  • Chapter 12: The Role of the AT2R in Vascular Remodeling
    • Abstract
    • Introduction
    • The Theoretical Concept of the Role of AT2R in Vascular Remodeling
    • AT2R and Hypertension-Induced Vascular Remodeling
    • AT2R and Atherosclerosis
    • AT2R and Aortic Aneurysm
    • Conclusion
  • Chapter 13: The AT2 Receptor and Inflammation
    • Abstract
    • Introduction
    • AT2R Signaling in Inflammation
    • Inflammation in Cardiovascular Disease and the Role of the AT2 Receptor
    • Inflammation in Autoimmune Disease and the Role of the AT2 Receptor
    • Conclusions
  • Chapter 14: The AT2 Receptor and Interacting Proteins (ATIPs) in Cancer
    • Abstract
    • Acknowledgments
    • The Renin–Angiotensin System and Cancer
    • The AT2 Receptor and Cancer
    • AT2 Receptor-Interacting Proteins (ATIPs) and Cancer
  • Chapter 15: AT2R and Sympathetic Outflow
    • Abstract
    • Acknowledgments
    • Introduction
    • AT2R Ontogeny in Rodent Brain
    • Effect of AT2R Activation on Neuronal Electrophysiological Characteristics
    • AT2R and Sympathetic Regulation in Normal States
    • Effects of the AT2R on Sympathetic Outflow in Pathological Conditions and Therapeutic Potential
    • Conclusion and Perspectives
  • Chapter 16: Metabolic Effects of AT2R Stimulation in Adipose Tissue
    • Abstract
    • Introduction
    • Metabolic Function of AT2R: The Lessons from ARBs
    • Metabolic Function of AT2R: The Lessons from AT2R-Deficient Mice
    • Metabolic Function of AT2R: Experiments with Direct AT2R Stimulation
  • Chapter 17: Sex Differences in AT2R Expression and Action
    • Abstract
    • Basis for Sex Differences in Function
    • Regulation of Arterial Pressure and Renal Function
    • Evidence for a Differential Role for the AT2R in Other Disease Conditions
    • Reproduction
    • Conclusion
  • Chapter 18: Discovery of Nonpeptide, Selective AT2 Receptor Agonists
    • Abstract
    • Acknowledgments
    • Selective Drug-like AT2R Agonists from Nonpeptide, Nonselective AT1/AT2 Receptor Ligands
    • Selective Drug-like AT2R Agonists from the Nonselective Parent Peptide Ang II
    • Conversion of AT2R Agonists to AT2R Antagonists
  • Chapter 19: Angiotensin-Based Peptides as AT2R Agonists
    • Abstract
    • Acknowledgments
    • Introduction
    • Endogenous Angiotensin Peptides
    • Synthetic Peptides
    • Conclusions
  • Chapter 20: Potential Clinical Application of Angiotensin 2 Receptor Agonists
    • Abstract
    • Introduction
    • Preclinical Testing
    • Investigational New Drug Application
    • Clinical Trials
    • Potential Therapeutic Indications for AT2R Agonists
    • Conclusion
  • Chapter 21: Angiotensin-(1-7) and Mas: A Brief History
    • Abstract
    • Introduction
    • Discovery of Mas: Is It a Proto-Oncogene?
    • Functions of Mas: Is It an Ang II Receptor?
    • Mas, Its Antisense RNA, and Imprinting
    • Mas Expression
    • Mas Functions: Mas-Deficient Mice
    • Discovery of Ang-(1-7)
    • Closing the Gap: Mas Is an Ang-(1-7) Receptor
  • Chapter 22: Animal Models with a Genetic Alteration of the ACE2/Ang-(1-7)/Mas Axis
    • Abstract
    • Introduction
    • Transgenic Animal Technology: A Brief Update
    • Transgenic and KO Rodent Models of the ACE2/Ang-(1-7)/Mas Axis
    • Conclusions and Outlook
  • Chapter 23: Mas Signaling: Resolved and Unresolved Issues
    • Abstract
    • Acknowledgments
    • Introduction
    • Expression of Mas
    • Mas as a GPCR
    • Early Discovery of Mas and Its Signaling Pathways
    • Identifying Ang-(1-7) Targets Through Proteomics
    • Ang-(1-7)/Mas Signaling Through Akt
    • Ang-(1-7)/Mas Signaling and Nitric Oxide Production
    • Mas and MAPK Signaling
    • Mas and RhoA
    • Biological Significance of Mas Signaling: Insights from Mas-Knockout Mice
    • Unresolved Issues
    • Conclusions
  • Chapter 24: Mas/AT2 Cross Talk
    • Abstract
  • Chapter 25: ACE2 Cell Biology, Regulation, and Physiological Functions
    • Abstract
    • Introduction
    • ACE2: Discovery and Basic Biology
    • ACE2 Regulation
  • Chapter 26: Mas in Myocardial Infarction and Congestive Heart Failure
    • Abstract
    • Myocardial Infarction and Congestive Heart Failure
    • Renin–Angiotensin System and Cardiac Remodeling
    • Inflammatory Phase
    • Proliferative Phase
    • Maturation Phase
  • Chapter 27: Mas Receptor: Vascular and Blood Pressure Effects
    • Abstract
  • Chapter 28: Mas and Neuroprotection in Stroke
    • Abstract
    • Introduction
    • Neuroprotection and the RAS
    • Mechanisms of Protection
    • Translation
    • Conclusion
  • Chapter 29: Mas in the Kidney
    • Abstract
    • Introduction
    • Role of ACE2/Ang-(1-7)/Mas in Renal Physiology
    • Physiopathological Role of ACE2/Ang-(1-7)/Mas in Renal Diseases
    • Concluding Remarks
  • Chapter 30: Mas and Inflammation
    • Abstract
    • Introduction
    • ACE2/Ang-(1-7)/Mas Axis in Cytokine Regulation and Cellular Recruitment
    • ACE2/Ang-(1-7)/Mas Axis and Fibrogenic Pathways
    • Concluding Remarks
  • Chapter 31: ACE2 and Glycemic Control
    • Abstract
    • ACE2/ANG-(1-7)/MAS: Role in Glycemic Control
    • ADAM17: A Potential Mechanism for ACE2 Shedding?
    • Perspective
  • Chapter 32: Angiotensin-(1-7) and Cancer
    • Abstract
    • Historical Perspective
    • Ang-(1-7) in Lung Cancer: Role in Proliferation and Angiogenesis
    • Ang-(1-7) in Breast Cancer: Role in Tumor Fibrosis
    • Ang-(1-7) in Prostate Cancer: Role in Regulation of Angiogenic Factors and Metastasis
    • Ang-(1-7) and Clinical Trials
    • Conclusion
  • Chapter 33: Mas and the Central Nervous System
    • Abstract
    • Mas Receptor Distribution in the Brain
    • Mas Receptor-Triggered Actions in the Central Nervous System
    • Mas Receptor and Central Neurotransmitters
    • Concluding Remarks
  • Chapter 34: Role of the Alternate RAS in Liver Disease and the GI Tract
    • Abstract
    • Introduction
    • The Classic RAS and Liver Fibrosis
    • ACE Inhibitors and AT1R Blockers in the Treatment of Liver Fibrosis
    • The Alternate RAS and Liver Fibrosis
    • Role of the RAS in Hepatic Resistance and Portal Hypertension
    • Role of the Alternate RAS in the Gut
    • Conclusion
  • Chapter 35: Metabolic Role of Angiotensin-(1-7)/Mas Axis
    • Abstract
    • Introduction
    • Ang-(1-7)/Mas Modulating Insulin Effects and Signaling
    • Liver Metabolic Effects of Ang-(1-7)/Mas Axis
    • New Metabolic Remarks and Perspectives
  • Chapter 36: Mas and the Reproductive System
    • Abstract
    • Introduction
    • Mas and the Female Reproductive System
    • Mas and the Male Reproductive System
    • Summary and Perspectives
  • Chapter 37: ACE2/Ang-(1-7)/Mas Axis and Physical Exercise
    • Abstract
    • Protective Effects of Physical Exercise
  • Chapter 38: Angiotensin-Converting Enzyme 2/Angiotensin-(1-7)/Mas Receptor Axis: Emerging Pharmacological Target for Pulmonary Diseases
    • Abstract
    • Introduction
    • Evidence for the Existence of Vasodeleterious and Vasoprotective Axes of the RAS in the Lungs
    • The ACE2/Ang-(1-7)/Mas Axis in Pulmonary Diseases
    • The ACE2/Ang-(1-7)/Mas Axis Protects Against ARDS and PAH
    • The ACE2/Ang-(1-7)/MAS Axis in PF
    • Therapeutic Strategies to Activate the ACE2/Ang-(1-7)/Mas Axis
    • ACE2 Activators
    • Strategies Targeting Ang-(1-7)
    • Mas Receptor Agonists
    • Future Perspectives
    • Conclusions
  • Chapter 39: Nanocarriers for Improved Delivery of Angiotensin-(1-7)
    • Abstract
    • Introduction
    • Liposome Formulations of Ang-(1-7)
    • Cyclodextrin-Based Oral Formulation of Ang-(1-7)
    • Conclusion
  • Chapter 40: Mas Agonists
    • Abstract
    • Introduction
    • Mas Agonists
    • Conclusions
  • Chapter 41: Preclinical and Clinical Development of Angiotensin Peptides (Mas/Ang(1-7)/ACE-2): Future Clinical Application
    • Abstract
    • Introduction
    • The Renin–Angiotensin System in Bone Marrow and Hematopoiesis
    • Clinical Development of A(1-7) for Hematopoietic Indications
    • Conclusions
  • Index


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© Academic Press 2015
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About the Editor

Thomas Unger

Affiliations and Expertise

MD, PhD, Professor & Scientific Director, CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands

U. Muscha Steckelings

Affiliations and Expertise

MD, PhD, Associate Professor, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

Robson Souza dos Santos

Affiliations and Expertise

MD, PhD, Professor, Federal University of Minas Geriais, Minas Geriais, Brazil

Ratings and Reviews