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Textbook of Nephro-Endocrinology

Textbook of Nephro-Endocrinology

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Textbook of Nephro-Endocrinology

2,074 pages
Nov 28, 2017


Textbook of Nephro-Endocrinology, Second Edition, continues to be the definitive translational reference in the field of nephro-endocrinology, investigating both the endocrine functions of the kidneys and how the kidney acts as a target for hormones from other organ systems. It offers researchers and clinicians expert analyses of nephro-endocrine research and translation into the treatment of diseases such as anemia, chronic kidney disease (CKD), rickets, osteoporosis, and hypoparathyroidism.

Changes to this edition include new chapters focused on hypercalcemia/hypocalcemia and the interaction of dialysis, chronic renal disease, and endocrine diseases. All chapters have been updated to include more preclinical data and more tables and schema that help translate this data into clinical recommendations. The section on hormones and renal insufficiency discusses insulin/diabetes, growth hormone, sex steroids, thyroid hormone, acid–base disturbances, and pregnancy.

  • Presents a uniquely comprehensive and cross-disciplinary look at all aspects of nephro-endocrine disorders in one reference
  • Investigates both the endocrine functions of the kidneys and how the kidney acts as a target for hormones from other organ systems
  • Offers clear translational presentations by the top endocrinologists and nephrologists in each specific hormone or functional/systems field
  • Features new and updated chapters that include more tables and schema to help translate preclinical data into clinical recommendations
Nov 28, 2017

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Textbook of Nephro-Endocrinology - Academic Press

Textbook of Nephro-Endocrinology

Second Edition


Ajay K. Singh

Gordon H. Williams

Table of Contents

Cover image

Title page


List of Contributors


Chapter 1. Physiology and Regulation of the Renin–Angiotensin–Aldosterone System

1. The Classical Circulating Renin–Angiotensin System

2. Renin Biosynthesis and Secretion

3. The (Pro)Renin Receptor

4. Angiotensin-Converting Enzyme

5. The ACE-2/Angiotensin (1-7)/Mas Receptor Pathway

6. AT1 Receptors

7. AT2 Receptors

8. Newly Discovered Components and Actions of the Renin–Angiotensin System

9. Angiotensin Receptor Heterodimerization

10. Tissue Renin–Angiotensin Systems

11. Intrarenal Renin–Angiotensin System

12. Brain Renin–Angiotensin System

13. Vascular Tissue Renin–Angiotensin System

14. Cardiac Renin–Angiotensin System

15. Subcellular Renin–Angiotensin Systems

16. Aldosterone and Mineralocorticoid Receptors

17. Clinical Effects of the Renin–Angiotensin–Aldosterone System

18. Summary

Chapter 2. The Renin–Angiotensin–Aldosterone System and the Kidney

1. Introduction

2. Historical Background

3. Overview of the Renin–Angiotensin System Pathway

4. Physiologic Effects of Renin–Angiotensin System

5. Renin–Angiotensin System in Human Disease

6. Conclusion

Chapter 3. The Renin–Angiotensin System and the Heart

1. Introduction

2. Cardiac RAS

3. Significance of the RAS on Cardiac Function

4. Conclusions

Chapter 4. Renin–Angiotensin Blockade: Therapeutic Agents

1. Introduction

2. Therapeutic Classes

3. Pharmacology

4. Chronotherapeutics With Renin–Angiotensin System Inhibitors

5. Direct Renin Inhibitors

6. Hemodynamic Effects of RAS Inhibitors

7. Additional Pathway Considerations and Mechanism of Action for RAS Inhibitors

8. Blood Pressure Lowering Effect

9. Renin-Angiotensin System Inhibitors With Other Agents

10. Side Effects Particular to Angiotensin-Receptor Blockers

11. Side Effects Unique to Direct Renin Inhibitors

12. Side Effects Unique to ACE Inhibitors

13. Select Side Effect Common to All Renin-Angiotensin System Inhibitors

Chapter 5. Vasopressin in the Kidney—Historical Aspects

1. Introduction

2. Hypothalamus

3. Vasopressin Receptors

4. Aquaporins

5. Vasopressin-Regulated Urea Transport

6. Nephrogenic Diabetes Insipidus

7. Vaptans

8. Summary

Chapter 6. Molecular Biology and Gene Regulation

1. Introduction

2. AVP Synthesis, Storage, and Release

3. Vasopressin Receptors

4. Cellular Regulation of Water, Electrolyte, and Mineral Reabsorption

5. Vasopressin, Renal Hemodynamics, and Blood Pressure

Chapter 7. Vasopressin Antagonists in Physiology and Disease

1. Introduction

2. Physiologic Antagonists

3. Vasopressin Antagonists and Their Role in the Treatment of Water-Retaining Disorders

4. Are Vasopressin Antagonists Safe?

5. Summary and Unanswered Questions

Chapter 8. Diabetes Insipidus and Syndrome of Inappropriate Antidiuretic Hormone

1. Introduction

2. Diabetes Insipidus and Syndrome of Inappropriate Antidiuretic Hormone

3. Hyponatremic Encephalopathy

Chapter 9. The Cardiac Natriuretic Peptide System: Linking the Heart and Kidney in Cardiorenal Homeostasis and Therapeutics

1. Natriuretic Peptides

2. Natriuretic Peptide Therapeutics

3. Designer Natriuretic Peptides for Cardiorenal Disease

4. Neprilysin and Neprilysin Inhibition

5. Neprilysin Inhibition as a Therapeutic Strategy for Targeting the Cardiorenal Axis

6. Future Directions

Chapter 10. Aldosterone’s Mechanism of Action: Genomic and Nongenomic Signaling

1. Introduction

2. The Mineralocorticoid Receptor

3. Genomic Actions of Aldosterone

4. Nongenomic Actions of Aldosterone

5. Epigenetic Effects

6. Mineralocorticoid Receptor Modulators

7. Novel Mineralocorticoid Receptor Antagonists

8. Conclusions

Chapter 11. Erythropoietin: An Historical Overview of Physiology, Molecular Biology, and Gene Regulation

1. Introduction

2. Hormonal Regulation of Erythropoiesis

3. Identification of the Site of Erythropoietin Production

4. Assays of Erythropoietin

5. Isolation and Characterization of Erythropoietin

6. Erythropoietin Effector Mechanisms

7. Regulation of Erythropoiesis by Hypoxia

8. Regulatory Elements of Erythropoietin Gene

9. Erythropoietin—The Paradigm for Gene Regulation by Hypoxia

10. Hypoxia-Inducible Factor

11. The Elusive Nature of the Oxygen Sensor

12. Degradation of Hypoxia-Inducible Factor by the Ubiquitin–Proteosomal Pathway

13. Targeting of Hypoxia-Inducible Factor by the von Hippel–Lindau E3 Ubiquitin Ligase

14. Regulation of the Hypoxia-Inducible Factor–von Hippel–Lindau Interaction

15. The Hypoxia-Inducible Factor Hydroxylases as Oxygen Sensors

16. Disruption of the Oxygen-Sensing Pathway in Cancer

17. Disruption of the Oxygen-Sensing Pathway in Hereditary Polycythemia

18. Pharmacological Manipulation of Hypoxia-Inducible Factor

19. Summary

Chapter 12. Erythropoiesis: The Roles of Erythropoietin and Iron

1. Erythropoiesis: An Overview

2. Role of Erythropoietin in Erythropoiesis

3. Role of Iron in Erythropoiesis

Chapter 13. Development of Recombinant Erythropoietin and Erythropoietin Analogs

1. Introduction

2. History of Recombinant Human Erythropoietin

3. Biosimilar Erythropoietins

4. Potential Strategies for Modifying Erythropoietin to Create New Erythropoietin Analogs

5. Darbepoetin Alfa

6. Continuous Erythropoietin Receptor Activator

7. Small Molecule Erythropoiesis-Stimulating Agents

8. Other Strategies for Stimulating Erythropoiesis

9. Conclusions

Chapter 14. Insulin Resistance and the Metabolic Syndrome in Chronic Renal Disease

1. Introduction

2. Historical Perspective

3. Cellular Mechanisms of Insulin Secretion and Action

4. Clinical Physiology of Insulin Resistance

5. Measurement of Insulin Resistance

6. Metabolic Syndrome

7. Pathogenesis of Insulin Resistance in Chronic Kidney Disease

8. Regulation of Renal Glucose Production

9. Syndromes of Severe Insulin Resistance

10. Treatment

11. Management of Diabetes in Chronic Kidney Disease

12. Hyperglycemia Associated With Renal Transplantation

13. Conclusions

Chapter 15. Growth Hormone

1. Growth Hormone and Insulin-Like Growth Factor-1 in Renal Failure

2. Pediatric Implications: Growth Failure and the GH/IGF-1 Axis in CKD

3. Adult Implications: Myriad Effects of Disturbed GH/IGF-1 Axis in CKD

4. Effects of Recombinant Growth Hormone Treatment in Renal Failure

5. The Horizon for Improving Growth and Anabolism in Renal Failure

6. Summary

Chapter 16. Sexual Dysfunction in Men and Women With Chronic Kidney Disease

1. Introduction

2. Sexual Dysfunction in Uremic Men

3. Evaluation of Sexual Dysfunction in the Uremic Man

4. Treatment of Sexual Dysfunction in the Uremic Man

5. Outcomes Associated With Hypogonadism and Treatment

6. Sexual Dysfunction in Uremic Women

7. Treatment

Chapter 17. Metabolic Acidosis of Chronic Kidney Disease

1. Introduction

2. Regulation of Acid–Base Balance With Normal Renal Function and Chronic Kidney Disease

3. Acid–Base Production

4. Renal Bicarbonate Generation

5. Cellular Buffering

6. Renal Tubular Bicarbonate Reabsorption

7. Hormonal Regulation of Acid–Base Balance With Normal Renal Function and CKD

8. Aldosterone

9. Angiotensin II

10. Parathyroid Hormone

11. Glucocorticoids

12. Antidiuretic Hormone

13. Glucagon

14. Endothelin

15. Insulin

16. Growth Hormone and IGF-1

17. Clinical Characteristics of the Metabolic Acidosis of Chronic Kidney Disease

18. Serum Electrolyte Pattern

19. Renal Tubular Bicarbonate Generation and Urinary Acidification

20. Clinical Characteristics of Acid–Base Parameters in Dialysis Patients

21. Effects of Metabolic Acidosis of CKD on Cellular Function

22. Exacerbation or Production of Bone Disease

23. Muscle Wasting

24. Reduced Albumin Synthesis

25. Acceleration of Progression of CKD

26. Exacerbation or Development of Cardiac Disease

27. Impaired Glucose Homeostasis and Lipid Metabolism

28. Leptin

29. Accumulation of β2-Microglobulin

30. Growth Hormone and Thyroid Function

31. Inflammatory Response

32. Treatment of the Metabolic Acidosis of CKD

Chapter 18. Pregnancy and the Kidney

1. Normal Pregnancy

2. Preeclampsia and HELLP Syndrome

3. Other Hypertensive Disorders of Pregnancy

4. Renal Failure in Pregnancy


Chapter 19. Vitamin D: Molecular Biology and Gene Regulation

1. Vitamin D

2. The 1,25-Dihydroxyvitamin D/Vitamin D Receptor Complex

3. Relevance of 1,25-Dihydroxyvitamin D/Vitamin D Receptor Actions in Health and in Kidney Disease

4. Concluding Remarks

Chapter 20. Clinical Syndromes of Vitamin D and Phosphate Dysregulation

1. Introduction

2. Metabolism

3. Transport

4. Mechanism of Action

5. Functions of Vitamin D

6. Recommended Dietary Allowance Guidelines for Vitamin D

7. Vitamin D Dysregulation: Epidemiology of Insufficiency and Toxicity States

8. Skeletal Manifestations of Vitamin D Dysregulation

9. Looking Beyond the Bones: Extraskeletal Manifestations of Vitamin D Dysregulation

10. Vitamin D Toxicity

11. Conclusion

Chapter 21. Molecular Biology of Renin and Regulation of Its Gene

1. Introduction

2. Production and Activation of Renin

3. Renin Gene Structure and Regulation

4. Renin Gene Mutation and Disease

5. Future Perspectives

Chapter 22. Vitamin D and the Kidney: Introduction and Historical Perspective

1. Introduction

2. Vitamin D

3. Role of Vitamin D in Kidney Disease

4. Role of Vitamin D in Other Disease States

Chapter 23. Extrahematopoietic Actions of Erythropoietin

1. The Biology of Erythropoietin

2. Examples of Nonerythropoietic Activities of EPO in Different Tissues

Chapter 24. Regulation of Aldosterone Production

1. Introduction

2. Aldosterone Biosynthesis

3. Factors Regulating Aldosterone Production

4. Adrenocorticotropic Hormone

5. Diseases of Aldosterone Production

6. Conclusions

Chapter 25. Aldosterone and Its Cardiovascular Effects

1. Introduction

2. Aldosterone and the Heart

3. Aldosterone and Brain

4. Aldosterone and Renal Disease

5. Potential Molecular Pathways Mediating the Adverse Vascular Effects of Aldosterone

6. Therapeutic Considerations

7. Conclusions

Chapter 26. Aldosterone: History and Introduction

1. Early History of Aldosterone

2. Aldosterone and Mineralocorticoid Receptor in Clinical Medicine

3. Mineralocorticoid Receptor Antagonists

Chapter 27. Thyroid Status in Chronic Renal Failure Patients

1. Epidemiology of Thyroid Dysfunction in Kidney Disease

2. Thyroid Physiology

3. Thyroid Functional Test Derangements in Kidney Disease

4. Potential Mechanisms Linking Thyroid and Kidney Disease

5. Thyroid Dysfunction and Outcomes

6. Treatment of Thyroid Dysfunction

7. Future Directions

Chapter 28. Aldosterone/Mineralocorticoid Receptors and Their Renal Effects: Molecular Biology and Gene Regulation

1. Introduction

2. Aldosterone-Binding Sites and the Mineralocorticoid Receptor

3. Molecular Biology of the Mineralocorticoid Receptor

4. Genomic Structure and Organization

5. Posttranslational Modifications of the Mineralocorticoid Receptor

6. Oligomeric Structure of Steroid Receptors

7. Cytoplasmic-Nuclear Shuttling of Steroid Receptors

8. Mineralocorticoid Receptor Selectivity

9. Distribution of the Mineralocorticoid Receptor in the Nephron

10. Proteins Induced by Aldosterone in Transport Epithelia

11. Nongenomic Effects of Aldosterone in the Kidney

12. Cross Talk of the Mineralocorticoid Receptor With Membrane Receptors

13. Aldosterone Effects Mediated by GPER (GPR30)

14. Renal Nongenomic Effects of Aldosterone

15. Physiological and Pharmacological Role of Antagonists of the Mineralocorticoid Receptor in Human Physiology and Pathology

16. Conclusions

Chapter 29. The History of the Renin–Angiotensin System

1. Introduction

2. The 20th Century

3. The 21st Century

4. The Dream to Be Normotensive and Drug Free

5. Conclusion

Chapter 30. Molecular Biology of Parathyroid Hormone

1. Biosynthesis and Metabolism

2. Parathyroid Hormone Receptors

3. Mechanisms of Parathyroid Hormone Binding and Parathyroid Hormone Receptor Signaling

4. Physiological Actions of Parathyroid Hormone

5. Disordered Parathyroid Hormone Regulation in Chronic Kidney Disease

Chapter 31. Endocrine Regulation of Phosphate Homeostasis

1. Introduction

2. Phosphate Homeostasis

3. Endocrine Regulatory Factors

4. Dysregulation of Phosphate Homeostasis

5. Conclusion



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List of Contributors

Gail K. Adler,     Harvard Medical School, Boston, MA, United States

S. Ananth Karumanchi,     Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States

Rose Ayoob,     The Ohio State University College of Medicine, Columbus, OH, United States

Juan C. Ayus

Universidad Austrar, Buenos Aires, Argentina

University of California Irvine School of Medicine, Irvine, CA, United States

George Bakris,     University of Chicago Medicine, Chicago, IL, United States

Rene Baudrand,     Pontificia Universidad Catolica de Chile, Santiago, Chile

Tomas Berl,     University of Colorado, Aurora, CO, United States

Wendy B. Bollag,     Medical College of Georgia, Augusta, Georgia

Michael Brines,     Araim Pharmaceuticals, Tarrytown, NY, United States

Alex J. Brown,     Washington University School of Medicine, St Louis, MO, United States

Ronald B. Brown,     University of Waterloo, Waterloo, ON, Canada

John C. Burnett Jr.,     Mayo Clinic and Foundation, Rochester, MN, United States

Robert M. Carey,     University of Virginia Health System, Charlottesville, VA, United States

Daniel F. Catanzaro,     Hofstra Northwell School of Medicine, Hempstead, NY, United States

Veeraish Chauhan,     Renal Hypertension Center, Bradenton, FL, United States

Yang Chen,     Mayo Clinic and Foundation, Rochester, MN, United States

Adriana S. Dusso,     Washington University School of Medicine, St Louis, MO, United States

Carolyn M. Ecelbarger,     Georgetown University, Washington, DC, United States

Carlos M. Ferrario,     Wake Forest University School of Medicine, Winston-Salem, NC, United States

Peter A. Friedman,     University of Pittsburgh School of Medicine, Pittsburgh, PA, United States

Rajesh Garg,     Harvard Medical School, Boston, MA, United States

Celso E. Gomez-Sanchez

G.V. Sonny Montgomery VA Medical Center, Jackson, MS, United States

University of Mississippi Medical Center, Jackson, MS, United States

Elise P. Gomez-Sanchez

G.V. Sonny Montgomery VA Medical Center, Jackson, MS, United States

University of Mississippi Medical Center, Jackson, MS, United States

Koro Gotoh,     Oita University, Oita, Japan

Carlos M. Isales,     Medical College of Georgia, Augusta, Georgia

Sahir Kalim,     Massachusetts General Hospital, Boston, MA, United States

Benjamin Ko,     University of Chicago Medicine, Chicago, IL, United States

Jeffrey A. Kraut

VA Greater Los Angeles Health Care System, Los Angeles, CA, United States

UCLA David Geffen School of Medicine, Los Angeles, CA, United States

Iain C. Macdougall,     King’s College Hospital, London, United Kingdom

John D. Mahan,     The Ohio State University College of Medicine, Columbus, OH, United States

Laura Meems,     Mayo Clinic and Foundation, Rochester, MN, United States

Joel Menard,     Faculté de médecine de Paris Descartes, Paris, France

Anastasia S. Mihailidou,     Kolling Institute, Northern Sydney Local Health District and The University of Sydney, Sydney, NSW, Australia

David R. Mole,     University of Oxford, Oxford, United Kingdom

Silvia Monticone

University of Torino, Torino, Italy

University of Michigan, Ann Arbor, MI, United States

Michael L. Moritz,     University of Pittsburgh School of Medicine, Pittsburgh, PA, United States

Glenn T. Nagami

VA Greater Los Angeles Health Care System, Los Angeles, CA, United States

UCLA David Geffen School of Medicine, Los Angeles, CA, United States

Sagar U. Nigwekar,     Massachusetts General Hospital, Boston, MA, United States

Shetal H. Padia,     University of Virginia Health System, Charlottesville, VA, United States

Biff F. Palmer,     University of Texas Southwestern Medical Center, Dallas, TX, United States

Akhil Parashar,     University of Iowa Hospitals and Clinics, Iowa City, IA, United States

Luminita Pojoga,     Harvard Medical School, Boston, MA, United States

William E. Rainey,     University of Michigan, Ann Arbor, MI, United States

Peter J. Ratcliffe,     University of Oxford, Oxford, United Kingdom

Mohammed S. Razzaque

Forsyth Institute, Cambridge, MA, United States

University of Rwanda School of Dentistry, Kigali, Rwanda

Harvard School of Dental Medicine, Boston, MA, United States

Lake Erie College of Osteopathic Medicine, Erie, PA, United States

Connie M. Rhee,     University of California Irvine School of Medicine, Orange, CA, United States

Jose R. Romero,     Harvard Medical School, Boston, MA, United States

Jeff M. Sands,     Emory University, Atlanta, GA, United States

Lynn E. Schlanger

Atlanta Veterans Affairs Medical Center, Atlanta, GA, United States

Emory University, Atlanta, GA, United States

Robert W. Schrier,     University of Colorado, Aurora, CO, United States

Hirotaka Shibata,     Oita University, Oita, Japan

Domenic A. Sica,     Virginia Commonwealth University Health System, Richmond, VA, United States

Donald C. Simonson,     Harvard Medical School, Boston, MA, United States

Ajay K. Singh,     Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States

Karan Sud,     Icahn School of Medicine at Mount Sinai St. Luke’s-West, New York, NY, United States

Swasti Tiwari

Sanjay Gandhi PGI, Lucknow, India

Georgetown University, Washington, DC, United States

Aaron J. Trask,     The Ohio State University College of Medicine, Columbus, OH, United States

Jean-Pierre Vilardaga,     University of Pittsburgh School of Medicine, Pittsburgh, PA, United States


During the last quarter century, dramatic increases in our understanding of the relationship of the renal and endocrine systems have occurred. While many of these advances have been documented in original and review articles and in some standard medical, renal or endocrine textbooks, a compilation of them in one text has not been available. Of interest, it was 25 years ago in 1983 that Dr. Michael Dunn edited what we believe was the last text on this subject. One of the editors of this text also served as a chapter author in Dunn’s book. Some subjects are similar between Dunn’s and the present text. Both have chapters on the renin–angiotensin system, aldosterone, antidiuretic hormone, parathyroid hormone and Vitamin D, insulin, thyroid hormone, female sex hormones and erythropoietin. In addition, the current textbook has chapters on atrial natriuretic peptides, growth hormone, acid–base balance and pregnancy.

During the past quarter century, there have been major increases in the tools needed to understand human physiology and pathophysiology. There has been substantial growth of bench tools, e.g., molecular biology, confocal microscopy and genetic manipulations of mice, available to understand fundamental mechanisms. Likewise there have been advances in the development of clinical tools unheard of 25 years ago, e.g., human genetics, high resolution imaging, advance statistics and bioinformatics. Because of these two facts, what could be written concerning the interaction of a hormone and the kidney in a single chapter 25 years ago now requires an entire section. Thus, instead of single chapters on the Renin–Angiotensin System, Aldosterone, Antidiuretic hormone, and Erythropoietin, the current text has entire sections devoted to these specific subjects.

Similar to Dunn’s textbook, the current one divides the subject matter into hormones produced by the kidney and hormones that act on the kidney. In addition the current textbook has a section on hormonal derangements and/or effects in individuals with chronic renal insufficiency. While the focus is on the actions and effects in humans, individual chapters draw on relevant preclinical data to more clearly understand the effects in humans. Each section begins with an historical introduction to the subject matter and then provides in depth discussions of it in one or more following chapters. The section on hormones and renal insufficiency discusses insulin/diabetes, growth hormone, sex steroids, thyroid hormone, acid–base disturbances and pregnancy. There are some subjects they could potential fit under the umbrella of the theme of this book that are not included. We apologize for any such omissions. However, space and time considerations limited our ability to include them.

The chapters are written to enlighten the novice and extend the knowledge base of the established investigator. None of the chapters are meant to be comprehensive of their subject matter as in many cases there are entire books written on the various topics. However, we believe the information contained herein will be of value to our audience of master’s or PhD trainees, medical students, students in other biomedical professional disciplines, scientists in industry, practicing clinical investigators and administrators in the broad fields of nephrology and endocrinology.

The editors wish to thank our devoted families who have patiently watched as we have spent countless hours working on this book. In particular, Ritu, Anika, Vikrum, Nikki and Mom Gita and in memory, JJ and Sanjay (Ajay Singh), and Dee Dee, Jeffrey, Christopher, Jonathan, Tarryn, Megan and Brenya (Gordon H. Williams); finally, we thank Michelle Deraney, Stephanie, Tran and Haris Lefteri for their support and dedication to this project.

Ajay K. Singh, MD

Gordon H. Williams, MD

Chapter 1

Physiology and Regulation of the Renin–Angiotensin–Aldosterone System

Robert M. Carey, and Shetal H. Padia     University of Virginia Health System, Charlottesville, VA, United States


The renin–angiotensin–aldosterone system (RAAS) is a major hormonal cascade in the control of blood pressure (BP), hypertension (HT), and tissue damage. The primary means by which the RAAS contributes to acute changes in extracellular fluid volume and BP homeostasis is by adjusting the level of renin in the circulation. Angiotensin II, the major effector peptide of the renin–angiotensin system (RAS), binds to two major receptors, AT1 and AT2, that generally oppose each other. During the past decade, several new pathways in the RAS have been discovered and/or clarified including a (pro)renin receptor, the functional properties of the AT2 receptor, and the ACE-2/angiotensin (1-7)/mas receptor pathway. The circulating RAS is the only one component of the overall RAS, and tissue RASs that operate independently of the circulating RAS have been identified and characterized, especially in the kidney. RAAS blockade has been central to the treatment of HT and its untoward outcomes such as heart failure, atrial fibrillation, coronary artery disease, and the prevention of progression to renal failure. Renin inhibition constitutes a new therapeutic modality in RAAS blockade.


11β-hydroxysteroid dehydrogenase type 2; Aldosterone; Angiotensin; Angiotensin (1-7); Angiotensin-converting enzyme-2; AT1 receptor; AT2 receptor; Mas receptor; Mineralocorticoid receptor; Prorenin; Regulation; Renin; Renin receptor; Renin–angiotensin system


1. The Classical Circulating Renin–Angiotensin System

2. Renin Biosynthesis and Secretion

3. The (Pro)Renin Receptor

4. Angiotensin-Converting Enzyme

5. The ACE-2/Angiotensin (1-7)/Mas Receptor Pathway

6. AT1 Receptors

7. AT2 Receptors

8. Newly Discovered Components and Actions of the Renin–Angiotensin System

9. Angiotensin Receptor Heterodimerization

10. Tissue Renin–Angiotensin Systems

11. Intrarenal Renin–Angiotensin System

12. Brain Renin–Angiotensin System

13. Vascular Tissue Renin–Angiotensin System

14. Cardiac Renin–Angiotensin System

15. Subcellular Renin–Angiotensin Systems

16. Aldosterone and Mineralocorticoid Receptors

17. Clinical Effects of the Renin–Angiotensin–Aldosterone System

18. Summary


The renin–angiotensin–aldosterone system (RAAS) is a major hormonal regulatory system in the control of blood pressure (BP) and hypertension (HT).¹–³ Several new components and pathways of the RAAS have been described during the past decade. In this chapter, these new components and pathways will be described and their potential clinical significance will be discussed.

1. The Classical Circulating Renin–Angiotensin System

The classical renin–angiotensin system (RAS) (Fig. 1.1) begins with the biosynthesis of the glycoprotein hormone, renin, by the juxtaglomerular (JG) cells of the renal afferent arteriole (Fig. 1.2). Renin is encoded by a single gene, and renin mRNA is translated into preprorenin, containing 401 amino acids.⁴,⁵ In the JG cell endoplasmic reticulum, a 20-amino-acid signal peptide is cleaved from preprorenin, leaving prorenin, which is packaged into secretory granules in the Golgi apparatus, where it is further processed into active renin by severance of a 46-amino-acid peptide from the N-terminal region of the molecule. Mature, active renin is a glycosylated carboxypeptidase with a molecular weight of ∼44  kDa. Active renin is released from the JG cell by a process of exocytosis involving stimulus-secretion coupling. In contrast, inactive prorenin is released constitutively across the cell membrane. Prorenin is converted to active renin by a trypsin-like proteolytic activation step.⁶

In the past, renin has been considered to have no intrinsic biological activity, serving solely as an enzyme catalytically cleaving angiotensinogen (Agt), the only known precursor of Ang peptides, to form the decapeptide Ang I (Fig. 1.1). Liver-derived Agt provides the majority of systemic circulating angiotensin (Ang) peptides, but Agt is also synthesized and constitutively released in other tissues, including the heart, vasculature, kidney, and adipose tissue. Angiotensin-converting enzyme (ACE), a glycoprotein (molecular weight 180  kDa) with two active carboxy-terminal enzymatic sites, hydrolyzes the inactive Ang I into biologically active Ang II⁷ (Fig. 1.1). ACE exists in two molecular forms: soluble and particulate. ACE is localized on the plasma membranes of various cell types, including vascular endothelial cells, the apical brush border (microvilli) of epithelial cells (e.g., renal proximal tubule cells), and neuroepithelial cells. In addition to cleaving Ang I to Ang II, ACE metabolizes bradykinin (BK), an active vasodilator and natriuretic autacoid, to BK (1-7), an inactive metabolite⁸ (Fig. 1.1). ACE, therefore, increases the production of a potent vasoconstrictor, Ang II, while simultaneously degrading a vasodilator, BK. ACE also metabolizes substance P into inactive fragments.

Figure 1.1  Schematic depiction of the classical renin–angiotensin system. Dashed line : short-loop negative feedback inhibition. ACE , angiotensin-converting enzyme; Agt , angiotensinogen; Ang , angiotensin; JG , juxtaglomerular.

Figure 1.2  Schematic representation of the renal juxtaglomerular apparatus showing the various components.

Unlike renin and Agt, which have relatively long plasma half-lives, Ang II and other Ang peptides are degraded within seconds by peptidases, collectively termed angiotensinases, at different amino acid sites, to form fragments, mainly des-aspartyl¹-Ang II (Ang III), Ang (1-7), and Ang (3-8) (Ang IV). Ang II is converted to Ang III by aminopeptidase A, and Ang III is converted to Ang IV by aminopeptidase N (APN). However, the expression levels and functional significance of these two critical enzymes, especially at the tissue level, are not completely understood, and the functional role of the peptide fragments produced is largely unknown.

The vast majority of cardiovascular, renal, and adrenal actions of Ang II are mediated by the Ang type-1 (AT1) receptor, a seven-transmembrane G protein–coupled receptor that is widely distributed in these tissues, which is coupled positively to protein kinase C and negatively coupled to adenylyl cyclase.⁹ As shown in Fig. 1.3, AT1 receptors mediate vascular smooth muscle cell contraction, aldosterone secretion, thirst, sympathetic nervous system stimulation, renal tubular Na+ reabsorption, and cardiac ionotropic and chronotropic responses, among many other actions. Ang II also binds to another cloned receptor, the Ang type-2 (AT2) receptor, but until recently the cell signaling mechanisms and functions of the AT2 receptor were unknown.⁹

2. Renin Biosynthesis and Secretion

Renin catalytic cleavage of Agt is the rate-limiting biochemical step in the RAS. The renal JG cell is thought to be the only source of circulating renin because following bilateral nephrectomy renin quantitatively disappears from the circulation.¹⁰ However, nephrectomy does not alter circulating levels of prorenin, indicating that nonrenal tissues (e.g., adrenal glands, testes, ovaries, placenta, and eyes) both produce and secrete prorenin into the circulation. In addition, many organs, such as the heart, can take up renin from the circulation by unclear mechanisms¹¹,¹² (see Chapter 14).

The primary means by which the RAAS contributes to acute changes in extracellular fluid volume and BP homeostasis is by varying the level of renin in the circulation. This process is mediated by active renin release from secretory granules of JG cells. A primary mechanism of renin release is the afferent arteriolar baroreceptor, which increases renin release when arterial (and renal) perfusion pressure decreases and vice versa. In addition, JG cells are innervated by sympathetic neurons, the activation of which stimulates norepinephrine release and subsequent stimulation of β1-adrenergic receptors triggering renin release. Therefore, as shown in Fig. 1.4, β1-adrenergic receptor blockade suppresses renin release by direct action at JG cells. JG cells also express both AT1 and AT2 receptors, and circulating Ang II participates in a short-loop negative feedback mechanism to inhibit renin release by binding to both of these receptors.¹³ Conversely, blockade of the RAS increases renin release and circulating renin levels (see Fig. 1.5 for ACE inhibitors and Fig. 1.6 for AT1 receptor blockers). Indeed, chronic RAS blockade by AT1 receptor antagonists or ACE inhibitors induces recruitment of new renin-secreting cells beyond the JG apparatus in the renal microvasculature, further augmenting renin secretion.¹⁴ Another renin secretory control mechanism is the macula densa segment of the early distal tubule, which relays a signal to the JG cell to increase renin release when a reduction in Na+ and/or Cl− in the distal tubule is detected.

Figure 1.3  Effects of angiotensin (Ang) II via Ang type-1 (AT 1 ) receptors. NO , nitric oxide; PAI-1 , plasminogen activator inhibitor-1; SNS , sympathetic nervous system.

Figure 1.4  Schematic representation of changes in the renin–angiotensin system in response to β 1 -adrenergic receptor blockade. Renin secretion and Ang peptide production are uniformly suppressed, as depicted in gray. ACE , angiotensin-converting enzyme; Agt , angiotensinogen; Ang , angiotensin; JG , juxtaglomerular.

Figure 1.5  Schematic representation of changes in the renin–angiotensin system in response to ACE inhibition. Ang II formation and bradykinin and substance P degradation are simultaneously reduced (gray) while renin biosynthesis and secretion are markedly increased due to inhibition of Ang II interaction with the AT 1 receptor on juxtaglomerular (JG) cells (short-loop negative feedback). ACE , angiotensin-converting enzyme; Agt , angiotensinogen; Ang , angiotensin.

Figure 1.6  Schematic representation of changes in the renin–angiotensin system in response to angiotensin AT 1 receptor blockers (ARBs). Renin biosynthesis and secretion are driven to high levels by interruption of short-loop negative feedback (gray), leading to markedly increased Ang II levels. ACE , angiotensin-converting enzyme; Agt , angiotensinogen; Ang , angiotensin; JG , juxtaglomerular.

3. The (Pro)Renin Receptor

Although renin has been considered as the enzyme responsible for cleaving the decapeptide Ang I from substrate Agt and has been thought to have no direct biological actions, recent studies demonstrate that renin can bind to human glomerular mesangial cell membranes in culture and that binding causes cell hypertrophy and increased levels of plasminogen activator inhibitor.¹⁵,¹⁶ The bound renin is not internalized or degraded. A (pro)renin receptor (PRR) has now been cloned from mesangial cells, and its functional significance remains in the process of being clarified.¹⁷ The receptor is a 350-amino-acid protein with a single transmembrane domain that specifically binds both renin and prorenin (Fig. 1.7).¹⁷ Binding induces the activation of the extracellular signal-related mitogen-activated protein (MAP) kinases (ERK 1 and ERK 2) associated with serine and tyrosine phosphorylation and a fourfold increase in the catalytic conversion of Agt to Ang I (Fig. 1.8). Activation of the PRR directly by prorenin or renin increases vacuolar H+-ATPase activity and ATP-dependent proton pumps that acidify intracellular compartments, including lysosomes, endosomes, and synaptic vesicles.¹⁸ The receptor is localized on renal mesangial cell membranes, the apical membranes of cortical collecting duct intercalated cells, and in the subendothelial layer of both coronary and renal arteries associated with vascular smooth muscle cells and colocalizes with renin.¹⁷ The receptor is also expressed in visceral adipocytes. In renal mesangial cells, the PRR mediates transforming growth factor-β production via MAP kinase phosphorylation (Fig. 1.9). In addition, MAP kinase activation occurs in collecting duct cells, vascular smooth muscle cells, monocytes, and neurons resulting in increased cell proliferation, production of transforming growth factor β1, upregulation of profibrotic factors plasminogen activator inhibitor-1, fibronectin, and collagen.¹⁹ Importantly, prorenin- and renin-PRR interaction requires pharmacological prorenin and renin concentrations; prorenin transgenic animals display an Ang II-dependent phenotype and PRR deletion is lethal, casting doubt as to whether prorenin- and renin-PRR interaction occurs in normal physiology.¹⁹ Although the possibility of a direct biological role of renin and prorenin via the PRR exists, the functional importance of this receptor other than catalytic conversion of Agt to Ang I awaits further investigation.

Figure 1.7  Schematic representation of the renin–angiotensin system depicting the interaction of prorenin and renin with a newly discovered and cloned (pro)renin receptor. ACE , angiotensin-converting enzyme; Agt , angiotensinogen; Ang , angiotensin.

Figure 1.8  Schematic illustration of the interaction of renin with angiotensinogen to cleave the decapeptide angiotensin I. Exposure to low temperature, acidification, or binding of renin to the (pro)renin receptor [(P)RR] displaces the prosegment peptide, allowing catalytic conversion of angiotensin I to occur in a reversible manner. Proteolytic cleavage of the prosegment peptide leads to irreversible catalytic cleavage. Agt , angiotensinogen; Ang , angiotensin. Adapted from Danser AHJ, et al. J Cardiovasc Pharmacol 2007;50:105–11, with permission.

Figure 1.9  Schematic representation of potential Ang II-independent direct effects of renin and/or prorenin mediated by the recently discovered (pro)renin receptor. Receptor activation results in phosphorylation of MAP kinases (P42/44), which mediate increased production of transforming growth factor-β (TGFβ), resulting in fibronectin, PAI-1, and collagen-1 formation in renal mesangial cells. These changes lead to increased contractility, hypertrophy, fibrosis, and apoptosis. Adapted from Huang Y, et al. Curr Hypertens Reports 2007;9:133–9, with permission.

4. Angiotensin-Converting Enzyme

ACE inactivates two vasodilator peptides, BK and kallidin. BK is both a direct and an indirect vasodilator via stimulation of NO and cGMP and also by the release of vasodilator prostaglandins, PGE2 and prostacyclin.²⁰ Thus, when an ACE inhibitor is employed (Fig. 1.5), not only the synthesis of Ang II is inhibited but also the formation of BK, NO, and prostaglandins is facilitated. ACE inhibition induces cross talk between the BK B2 receptor and ACE on the plasma membrane, abrogating B2 receptor desensitization and potentiating both the levels of BK and the vasodilator action of BK at its B2 receptor.²¹,²² Also, in the presence of ACE inhibition an alternative pathway of Ang II production via chymase may be activated (Fig. 1.5).²³,²⁴ The chymase pathway may serve as a major route of Ang II formation in the heart, especially in the presence of ACE inhibition.

5. The ACE-2/Angiotensin (1-7)/Mas Receptor Pathway

A second ACE, ACE-2, has recently been discovered (Fig. 1.10). ACE-2 is a zinc metalloproteinase consisting of 805 amino acids with significant sequence homology to ACE.²⁵ Unlike ACE, however, ACE-2 functions as a carboxypeptidase rather than a dipeptidyl-carboxypeptidase. In contrast to ACE, ACE-2 hydrolyzes Ang I to Ang (1-9), but the major pathway is the conversion of Ang II to Ang (1-7) (Fig. 1.10). ACE-2 also degrades BK to [des-Arg⁹]-BK, an inactive metabolite. In marked contrast to ACE, ACE-2 does not convert Ang I to Ang II and its enzyme activity is not blocked with ACE inhibitors. Thus, ACE-2 is effectively an inhibitor of Ang II formation by stimulating alternate pathways for Ang I and, particularly, Ang II degradation. ACE-2 has been localized to the cell membranes of cardiac myocytes, renal endothelial and tubule cells, and the testis. ACE-2 gene ablation does not alter BP but impairs cardiac contractility and induces increased Ang II levels, suggesting that ACE-2 may at least partially nullify the physiological actions of ACE.²⁴

The heptapeptide fragment of Ang II and Ang (1-7) (Fig. 1.10) has been discovered to have biological activity²⁶,²⁷ (see Chapter 14 for additional details). Ang (1-7) can be formed directly from Ang I by a two-step process involving conversion to Ang (1-9) by ACE-2 followed by conversion to Ang (1-7) by endopeptidases. However, as stated above, the major pathway for Ang (1-7) formation is directly from Ang II by the action of ACE-2 (Fig. 1.10). Interestingly, the major catabolic pathway for inactivation of Ang (1-7) is by ACE (Fig. 1.10). Thus, ACE inhibitor administration markedly increases the level of Ang (1-7).²⁸ The kidney is a major target organ for Ang (1-7). Although a specific Ang (1-7) receptor has not been cloned, the peptide is an endogenous agonist for the Mas oncogene, which mediates the majority of its actions (Fig. 1.10).²⁹ Ang (1-7) binds to and activates the mas receptor, inducing phosphatidylinositol 3-kinase/Akt pathway leading to activation of endothelial NO synthase, the consequent NO release–inducing vasodilation.³⁰,³¹ The peptide is formed in the kidney, where it has specific actions via a non-AT1 or non-AT2 receptor. These actions include increased GFR, inhibition of Na/K/ATPase, vasorelaxation, natriuresis, diuresis, and downregulation of AT1 receptors, all of which are blocked by the specific Ang (1-7) antagonist (D-Ala⁷)-Ang (1-7) and are mediated at least in part by NO and prostacyclin.³¹,³² Most of these renal effects of Ang (1-7) oppose those of Ang II via the AT1 receptor.

Figure 1.10  Schematic representation of the renin–angiotensin system depicting Ang II binding to both AT 1 and AT 2 receptors and the newly discovered ACE-2 pathway for conversion of Ang II directly to Ang (1-7), which interacts with the mas receptor to inhibit cell growth and stimulate vasodilation and natriuresis via prostaglandins and nitric oxide. Because Ang (1-7) is metabolized to inactive fragments by ACE, ACE inhibition results in increased Ang (1-7) levels. ACE , angiotensin-converting enzyme; Agt , angiotensinogen; Ang , angiotensin.

6. AT1 Receptors

Ang II, the major effector peptide of the RAS, binds to two major receptors AT1 and AT2, which generally oppose each other.⁹ The AT1 receptor is widely distributed in the vasculature, heart, and kidney.³³–³⁷ Actions of Ang II mediated by the AT1 receptor include vasoconstriction; SNS activation; aldosterone, vasopressin, and endothelin secretion; plasminogen activator inhibitor biosynthesis; platelet aggregation; thrombosis; cardiac contractility; superoxide formation; VSM growth; and collagen formation (Fig. 1.3). These actions are conducted by both G protein–coupled and G protein–independent pathways and involve phospholipases C, A2, and D activation; increased intracellular Ca++ and inositol 1,4,5-trisphosphate; activation of MAP kinases; ERKs and the JAK/STAT pathway; enhanced protein phosphorylation; and stimulation of early growth response genes.³⁸–⁴³ Tyrosine phosphorylation and stimulation of MAP kinase phosphorylation are the major intracellular signaling pathways for the AT1 receptor.⁴⁴ Ang II, via AT1 receptors, activates c-SRC generating reactive oxygen species (ROS) via NADPH oxidase (NOX1). Many of the detrimental tissue effects of Ang II, including vascular smooth muscle contraction, hyperplasia/hypertrophy, fibrosis, and inflammation, involve the actions of ROS on these intracellular signaling pathways.

7. AT2 Receptors

The second major Ang II receptor is the AT2 receptor (Fig. 1.11). AT2 receptors are highly expressed in fetal tissues but regress substantially in the postnatal period.³³ However, the AT2 receptor is still expressed at low copy in the adult vasculature, especially in the endothelium and renal vasculature, JG cells, glomeruli, and tubules.³³,⁴⁵ The AT2 receptor acts via the third intracellular loop by a Gi protein–mediated process involving stimulation of protein tyrosine phosphatases and reduction of ERK phosphorylation and activity.⁴⁶ The AT2 receptor also induces sphingolipid and ceramide accumulation.⁴⁷ A major mechanism of action of AT2 receptors is BK release (probably via kininogen activation through cellular acidification) with consequent NO and cGMP generation⁴⁸–⁵⁰ (Fig. 1.12). AT2 receptors can also stimulate NO directly without BK as an intermediate.⁵¹ The AT2 receptor mediates vasodilation, natriuresis, and inhibition of cell growth.²,⁵⁰ Ang III, not Ang II, appears to be the preferred agonist for AT2 receptor–mediated natriuresis.⁵² When the AT1 receptor is blocked, augmentation of renin release by inhibition of short-loop negative feedback leads to increased Ang II formation (Fig. 1.12). Increased levels of Ang II, while inhibited from binding to the AT1 receptor, are free to activate the unblocked AT2 receptor, potentially leading to vasodilation and/or natriuresis (Fig. 1.12). Acute studies in experimental animals have demonstrated that these beneficial effects of AT1 receptor blockers are mediated, at least acutely, by activation of AT2 receptors⁵³ (Fig. 1.13). Thus, clinically it was anticipated that AT1 receptor blockers would have a greater cardiovascular and renal protective effects than ACE inhibitors. This prediction has not been proven to be the case.⁵⁴ However, equivalent clinical efficacy of ACE inhibitors and AT1 receptor blockers does not test whether AT2 receptor activation participates in the beneficial actions of AT1 receptor blockade. AT2 receptors, similar to AT1 receptors, mediate short-loop negative feedback of renin biosynthesis and secretion at JG cells¹³ (Fig. 1.11).

Figure 1.11  Schematic rendition of the interaction of angiotensin II with the AT 1 and AT 2 receptors, both of which mediate negative feedback inhibition of renin release ( dashed lines ) at renal juxtaglomerular (JG) cells. ACE , angiotensin-converting enzyme; Agt , angiotensinogen; Ang , angiotensin.

Figure 1.12  Schematic depiction of the paracrine vasodilator cascade elicited by activation of AT 2 receptors by Ang II. AT 2 receptor activation can stimulate nitric acid (NO) production directly or can do so via increased levels of bradykinin (BK) via its B 2 receptor. Ang , angiotensin; cGMP , cyclic guanosine monophosphate; GTP , guanosine triphosphate; sGC , souble guanylate cyclase.

Figure 1.13  Schematic representation of changes in the renin–angiotensin system induced by AT 1 receptor blockade (ARBs). Ang II levels are increased by interruption of short-loop negative feedback on renin secretion ( dashed gray line ). Ang II is free to activate unblocked AT 2 receptors inducing vasodilation and natriuresis. ACE , angiotensin-converting enzyme; Agt , angiotensinogen; Ang , angiotensin; JG , juxtaglomerular.

8. Newly Discovered Components and Actions of the Renin–Angiotensin System

The traditional concept of the RAS has been that the initial peptide cleaved from Agt is Ang I and that all other Ang peptides are derived directly or indirectly from Ang I metabolism.² This concept has recently been challenged, however, by the discovery of Ang (1-12), a peptide containing a 2-amino-acid (Leu¹¹-Tyr¹²) C-terminal extension of Ang I.⁵⁵ Ang (1-12) has been demonstrated to be a peptide precursor of Ang II, and renin does not participate in Ang (1-12) formation or metabolism.⁵⁵,⁵⁶ In tissues such as the heart, instead of ACE, chymase is the major Ang (1-12) metabolizing enzyme.⁵⁶ The enzymes involved in the formation of Ang (1-12) from Agt are currently unknown (Fig. 1.14), and the physiological and pathophysiological roles of Ang (1-12) remain to be demonstrated.

Alamandine is a product of the catalytic hydrolysis of Ang (1-7), but the enzyme responsible for endogenous alamandine formation is unknown (Fig. 1.14). Interestingly, alamandine possesses many of the functional properties of Ang (1-7), including endothelium-dependent vasodilation that can be attenuated by NOS inhibitors.⁵⁷ Alamandine induces hypotensive and antifibrotic properties. However, its potential role in humans is unknown. Unexpectedly, administration of Mas receptor antagonist A-779 did not block alamandine-induced vasodilation, but alamandine-induced vasodilation was preserved in aortic rings of Mas-receptor null mice. However, alamandine-induced vasodilation was completely blocked by another Ang (1-7) antagonist D-Pro⁷-Ang (1-7).⁵⁷ This suggested that alamandine might bind to another Mas-related receptor, MrgD (Fig. 1.14). Indeed, alamandine binds to MrgD receptors in vitro and releases NO in MrgD- but not Mas-receptor transfected cells.⁵⁷ The alamandine-MrgD receptor axis currently appears to be an additional counterregulatory arm of the RAS, opposing actions mediated by AT1Rs. However, the role of this agonist/receptor complex in humans is uncertain.

9. Angiotensin Receptor Heterodimerization

Some of the actions of Ang II may be related to heterodimerization. If AT1 and AT2 receptors are expressed in the same cell, the physical association of these receptors on the cell membrane may inhibit the action of AT1 receptors in a ligand-independent manner.⁵⁸ Similarly, there is evidence for AT1 receptor and BK B2 receptor heterodimerization resulting in increased AT1 receptor effects via G-protein activation and AT2-B2 receptor heterodimerization resulting in increased cGMP formation.⁵¹,⁵⁹,⁶⁰

10. Tissue Renin–Angiotensin Systems

As discussed above, the circulating RAS is the only one component of the overall RAS. Tissue RASs that may operate completely independently of the circulating RAS have now been identified in the brain, kidney, heart, blood vessels, adipocytes, and adrenal gland. Given the independence of tissue RASs, it is possible that they are activated even when the circulating RAS is normal or suppressed. However, it has been difficult to show the relative roles of the intrarenal RAS as opposed to the systemic RAS. This issue has been considered important because the long-term regulation of BP has been thought to involve the kidney and the ability to sustain a hypertensive process chronically has been regarded as requiring renal Na+ retention. Indeed, the key sites that determine the level of BP could not be localized precisely using ACE inhibitors or AT1 receptor blockers, which inhibit the RAS in all tissues or by conventional gene-targeting experiments. Recent work, however, has helped clarify the tissue sites whereby the RAS regulates BP through a cross-transplantation approach in AT1A receptor-deficient mice.⁶¹ Rodents have two AT1 receptors: AT1A and AT1B receptors. The AT1A receptor is considered as the major AT receptor mediating the majority of actions of Ang II. In terms of expression, AT1A receptors predominate in most organs except the adrenal gland and regions of the central nervous system, wherein AT1B receptor expression is more predominant.⁶² Absence of AT1A receptors exclusively in the kidney, with normal receptors elsewhere, was sufficient to lower BP by about 20  mmHg.⁶¹ Thus, renal AT1 receptors were demonstrated to have a unique and nonredundant role in the control of BP homeostasis. As aldosterone levels were unaffected in these experiments, BP appears to be regulated by the direct action of AT1 receptors on kidney cells, independent of mineralocorticoids. However, in addition to the kidney, AT1 receptors outside the kidney were demonstrated to make an equivalent, unique, and nonredundant contribution to BP control; animals with a full complement of AT1A receptors in the kidney, but without AT1A receptors in extrarenal tissues, also had BP reductions of about 20  mmHg.⁵⁹ This finding was also independent of aldosterone levels. Taken altogether, this evidence indicates that AT1 receptors, either in the vasculature or the central nervous system, mediate the component of BP control that is independent of the kidney, at least in rodents. Because humans have only one form of the AT1 receptor, it is uncertain if a similar scenario applies to them.

Figure 1.14  Schematic depiction of the renin–angiotensin system components and selected actions. Newly described enzymatic pathways are shown by gray arrows and receptors are shown in boxes. ACE , angiotensin-converting enzyme; Agt , angiotensinogen; Ang , angiotensin; APA , aminopeptidase A; AT 1 R , angiotensin type-1 receptor; AT 2 R , angiotensin type-2 receptor; MasR , mas receptor; MrgD , mas -related G-protein–coupled receptor; PRR , (pro)renin receptor.

It is clear that Ang I and II are synthesized in tissue sites. Indeed, most, if not all, tissue Ang II is synthesized locally from tissue-derived Ang I.⁶³,⁶⁴ In addition, the beneficial actions of RAS blockers are most likely due to interference with tissue Ang II rather than Ang II in the circulation.⁶⁵ Although it was originally thought that the renin required for local Ang I synthesis was synthesized locally, studies in nephrectomized animal models proved that this was not the case.⁵⁸,⁶⁶–⁶⁸ In many tissues, such as the heart and blood vessel wall, local Ang I synthesis depends on tissue uptake of kidney-derived renin,⁵⁹ although this is still controversial (see Chapter 3). In other tissues such as adrenal gland and brain, renin may be synthesized locally.⁶⁰ In addition, prorenin, the inactive precursor of renin, may contribute to Ang I generation at tissue sites.⁶⁹,⁷⁰ This would require activation of prorenin to renin following uptake from the systemic circulation, unless the recently described PRR is involved.

Agt is synthesized predominantly in the liver, but local synthesis has also been claimed for the vasculature and adipocytes.⁷¹,⁷² It was formerly thought that kidney-synthesized Agt was the major or even exclusive source for intrarenal Ang II generation, but recent molecular studies have now refuted this concept. Selective renal knockout of Agt in mice indicates that Agt synthesized in the liver is the predominant or exclusive source of Ang peptides in the kidney.⁷³ Similarly, Ang II is formed mainly from hepatic Agt in the heart.⁷⁴

In summary, Ang II generation largely occurs in tissues but depends on renal renin and largely, if not exclusively, on hepatic Agt. Both renin and Agt diffuse into the interstitium where they are taken up, and Ang II is generated in the presence of ACE, almost universally expressed in cell membranes. Ang II rapidly binds to AT1 receptors and the angiotensin–receptor complex is rapidly internalized into the cell, where its signaling is initiated.

11. Intrarenal Renin–Angiotensin System

The intrarenal RAS was first recognized in the 1970s and early 1980s when selective intrarenal inhibition of the RAS was demonstrated to increase GFR and renal Na+ and water excretion.⁷⁵,⁷⁶ Since that time, the intrarenal RAS has increasingly been recognized as a fundamental system in the regulation of Na+ excretion and the long-term control of arterial BP.⁷⁷,⁷⁸ Indeed, there is growing recognition that inappropriate activation of the intrarenal RAS prevents the kidney from maintaining normal Na+ balance at normal arterial pressures and is an important cause of HT.⁷⁷–⁷⁹ Several experimental models support an overactive intrarenal RAS in the development and maintenance of HT.⁷⁷,⁷⁸,⁸⁰–⁸³ These include 2-kidney, 1-clip (2K1C) Goldblatt HT, Ang II-infused HT, transgenic rat (TGR) mRen2 HT with an extra renin gene, the spontaneously hypertensive rat (SHR) model, the remnant kidney hypertensive model, and several mouse models overexpressing the renin or Agt gene.⁷⁷,⁷⁸ Indeed, there is increasing recognition that in many forms of HT the intrarenal RAS is inappropriately activated, limiting the ability of the kidney to maintain Na+ balance when perfused at normal arterial pressure.⁸¹,⁸⁴,⁸⁵ In addition to Na+ and fluid retention and progressive HT, other long-term consequences of an inappropriately activated intrarenal RAS include renal, vascular, glomerular, and tubulointerstitial injury and fibrosis.⁷⁸,⁸⁶,⁸⁷

Evidence for overactivation of the intrarenal RAS in HT has accumulated for many of the components of the intrarenal RAS. In Ang II-dependent HT, renal vascular and glomerular AT1 receptors are downregulated but proximal tubule receptors are either upregulated or not significantly altered.⁷⁷,⁷⁸ In some forms of HT [e.g., 2K1C Goldblatt HT, Ang II-induced HT, and TGR (mRen2) HT], net intrarenal Ang II content is increased because of the intrarenal production of Ang II as well as increased uptake of the peptide from the circulation via an AT1 receptor–mediated process.⁷⁷,⁷⁸ A sustained increase in circulating Ang II causes progressive accumulation of Ang II within the kidney in these models. A substantial fraction of the increase in intrarenal Ang II is due to AT1 receptor–mediated endocytosis.⁷⁷,⁷⁸,⁸⁶ In the 2K1C Goldblatt model, intrarenal Ang II was elevated both in the clipped and nonclipped kidneys both during the development phase (1  week) and up to 12  weeks following clipping.⁶²,⁸⁸ These increases in intrarenal Ang II were present even in the absence of increased plasma Ang II.⁶² Renal interstitial Ang II levels also have been reported as elevated in several Ang II-dependent models of HT, including the 2-kidney, 1-wrap (2K1W) Grollman model and the Ang II-infused hypertensive model.⁵³,⁸⁹ However, measurements of renal tubular fluid Ang II have not demonstrated significant differences between control and hypertensive rats.⁹⁰,⁹¹ Because Ang II bound to the AT1 receptor is internalized by receptor-mediated endocytosis, endosomal accumulation of Ang II in renal cells has been studied in Ang II-infused HT. Endosomal Ang II was increased and endosomal Ang II accumulation was blocked by AT1 receptor blockade.⁹² At least some of the internalized Ang II remain intact and contribute to the increased total Ang II content as measured in renal cortical homogenates in this model.⁸⁵,⁸⁹ The internalized Ang II could be recycled and secreted, being available to act at plasma membrane AT1 receptors, or may act at cytosolic receptors, as have been described for vascular smooth muscle cells.⁷⁷,⁷⁸,⁹³ Another possibility is that Ang II could exert genomic effects in the nucleus as a part of the intracrine system.⁹³–⁹⁷ Because Ang II may exert positive feedback stimulation of Agt in mRNA, intracellular Ang II may upregulate Agt or renin gene expression in renal proximal tubule cells.⁹⁸

Agt is the only known precursor of Ang II, and most of the intrarenal Agt mRNA and protein are localized to the proximal tubule cell (Fig. 1.15), suggesting that intratubular Ang II is produced from locally formed Agt.⁹⁹,¹⁰⁰ However, as stated above, molecular studies of Agt knockout in the kidney now clearly demonstrate that during baseline conditions the liver is the main or even exclusive source of renal Agt.⁷³ Nevertheless, when the RAS is activated, it is possible that renal-derived Agt plays an increased role in Ang II synthesis. Both Agt and its metabolite Ang II derived from proximal tubule cells are secreted directly into the tubule lumen.¹⁰¹ In response to a 2-week infusion of Ang II, intrarenal Agt mRNA and protein were upregulated.⁹⁹,¹⁰⁰ Therefore, an intrarenal positive feedback loop is probably present whereby increased Ang II stimulates its requisite precursor, leading to markedly increased Ang peptide levels in HT.⁷⁷,⁷⁸

Figure 1.15  Light photomicrograph of the rat renal cortex demonstrating angiotensinogen protein (brown) by immunohistochemistry. Angiotensinogen within the kidney is synthesized largely in cortical proximal tubule cells.

Figure 1.16  Schematic representation of the intrarenal renin–angiotensin system, the most fully characterized of the independent tissue renin–angiotensin systems. AA , afferent arteriole; EA , efferent arteriole; JGA , juxtaglomerular apparatus. Adapted from Navar LG, et al. Hypertension 2002;39(2 Pt 2):316–22, with permission.

Renin is not only synthesized and secreted in the JG cells of the afferent arteriole but also by connecting tubules, indicating that renin is probably secreted into distal tubule fluid.¹⁰¹ Because intact Agt is present in urine, it is possible that some of the proximally formed Agt is converted to Ang II in the distal nephron.¹⁰¹,¹⁰² Indeed, Ang II infusion significantly increased urinary Agt in a time- and dose-dependent manner associated with increased renal Ang II levels.⁹⁸,¹⁰² Furthermore, collecting duct renin is upregulated by Ang II via the AT1 receptor.¹⁰³,¹⁰⁴ Therefore, several intrarenal mechanisms provide positive feedback control to enhance Ang II concentrations at both proximal and distal tubule sites, where Ang II has potent Na+-retaining actions.¹⁰⁵–¹⁰⁷ A schematic depiction of the intrarenal RAS is shown in Fig. 1.16.

In addition to aforementioned work suggesting the seminal role of kidney AT1 receptors in the production of HT, recent studies have demonstrated that production of renin and Agt in the proximal tubule can increase BP independently of the circulating RAS.¹⁰⁸ Transgenic mice expressing human Agt selectively in the proximal tubule via the kidney androgen-regulated protein promoter, when bred with mice expressing human renin systemically, had a 20  mmHg increase in BP despite having normal Ang II levels in plasma.¹⁰⁸ The increase in BP could be abolished with AT1 receptor blockade,¹⁰⁸ indicating an Ang II-dependent HT. This was the first demonstration of systemic HT from isolated renal tissue activation of the RAS.¹⁰⁸ Furthermore, when purely proximal tubule overexpression of both human renin and Agt was achieved, HT was also present, supporting the concept that intrarenal tubular RAS activation could induce HT.¹⁰⁸ In these studies, it was unclear whether Ang I was first generated within the proximal tubule cell from intracellular cleavage of Agt by renin or whether the renin and Agt interaction occurred in the tubule lumen after secretion.¹⁰⁸ Also, whether the HT was due to increased proximal or distal Na+ reabsorption, or both, remained unanswered.

Finally, it appears that the ability of Ang II to induce HT and cardiac hypertrophy resides exclusively in activation of AT1 receptors within the kidney to reduce urinary Na+ excretion. The basis for this principle is renal AT1A receptor cross-transplantation studies demonstrating that, in animals with renal but not systemic AT1A receptors, Ang II infusion was able to induce a hypertensive phenotype with cardiac hypertrophy. On the other hand, animals with systemic but not renal AT1A receptor expression were unable to mount a hypertensive or cardiac hypertrophic response to Ang II. The ability of Ang II to induce HT was directly via renal AT1A receptors and did not require an increase in aldosterone secretion. Therefore, the evidence strongly suggests that renal AT1 receptors, in glomeruli, blood vessels, and/or tubules, are critical for the development of Ang II-induced HT.¹⁰⁹ Furthermore, recent selective knockout studies show that Ang II-induced HT is specifically dependent on AT1A receptors in the proximal tubule.¹¹⁰ However, it is important to emphasize that these findings in experimental animals have been difficult to document in humans. Thus, the renal mechanisms by which Ang II induces HT in humans remain uncertain.

12. Brain Renin–Angiotensin System

Although many tissues express all of the RAS components necessary for the biosynthesis and action of Ang II, the ability of the tissues to actually produce Ang II and the specific role of locally generated Ang II have only been proven for the kidney³ and only in experimental animals. An independently functioning RAS in the brain remains controversial because the level of the rate-limiting component, renin, is extremely low and difficult to detect. There is no question that administration of exogenous Ang II centrally increases BP, sympathetic outflow, vasopressin release, drinking behavior, and attenuation of baroreceptor reflux activity and that these effects are blocked with AT1 receptor blockade.¹¹¹ In addition, specific brain nuclei clearly mediate Ang II responses, including the ventrolateral medulla, nucleus tractus solitarii, paraventricular nucleus, and subfornical organ, among several others.¹¹² Although all of the RAS components are present in various regions of the brain, renin expression in very low levels has been detected in the pituitary and pineal glands, choroid plexus, hypothalamus, cerebellum, and amygdala as well as other locations.¹¹¹ At the cellular level renin has recently been detected in both neuronal and glial tissues.¹¹³,¹¹⁴ If a neuronal source of renin is coupled with a glial source of Agt, Ang II could derive from secreted precursors in the extracellular space. However, recent studies have demonstrated colocalization of Agt with a novel nonsecreted form of renin, opening the door to intracellular Agt synthesis and possible action.⁹⁷,¹¹⁴

Because brain renin levels are low, investigators have searched for a renin-independent Ang II generating system in the brain. Many enzymes are present in the brain that can generate Ang II either from Ang I or directly from Agt, including trypsin, tonin, elastase, cathepsin C, kallikrein, chymase, and chymostatin-sensitive Ang II–generating enzyme.¹¹⁵

In addition to nonrenin pathways, some investigators have suggested the involvement of non-Ang II peptides, including Ang III, Ang IV, and Ang (1-7), as important regulators of BP.¹¹⁶ In particular, Ang III appears to have a prominent role.¹¹⁷ Aminopeptidase A (APA), which metabolizes Ang II to Ang III, is present in the brain.¹¹⁸ Ang II and Ang III are equally potent pressor substances when infused directly into the brain, and the pressor action of Ang II was abolished by preadministration of an APA inhibitor, suggesting that conversion to Ang III may be required.¹¹⁹,¹²⁰ Ang II and Ang III have equal affinity for the AT1 receptor and both also are agonists at the AT2 receptor. However, the Ang III–mediated increase in BP appears to be mediated by the AT1 receptor, as its action can be blocked with an AT1 receptor blocker. In addition, inhibition of endogenous brain Ang III formation by intracerebroventricular, but not intravenous, APA inhibitor induced a large, dose-dependent reduction in BP in conscious SHR and deoxycorticosterone acetate-salt rat, a RAS-independent model of HT.¹¹⁹,¹²⁰ On the other hand, administration of an inhibitor of APN, which metabolizes Ang III to Ang IV, into the brain induces a pressor effect that is abolished with an AT1 receptor blocker.¹¹⁹ Thus, increasing endogenous brain Ang III levels increases BP via the AT1 receptor. Moreover, the pressor action of an APN inhibitor could be blocked with an APA inhibitor, confirming the existence of an endogenous brain Ang III cascade in the control of BP.¹¹⁹ Finally, work employing nonmetabolizable analogs D-Asp¹-Ang II and D-Asp¹-Ang III demonstrated that Ang III is a centrally active agonist of the brain RAS.¹¹⁸

There is also evidence that Ang IV may be an endogenous ligand of the brain RAS. When Ang IV is overexpressed specifically in the brain, these transgenic mice developed HT that was abolished by an AT1 receptor antagonist.¹²¹ The role of Ang (1-7) as a counterregulatory peptide to the pressor actions of Ang II is the subject of current studies.¹¹⁵,¹¹⁶ These studies take on additional importance because of the recent discovery of ACE-2, which converts Ang II directly to Ang (1-7) and the identification of the Mas oncogene as an Ang (1-7) receptor. Furthermore, the receptor for renin and prorenin, which probably converts Agt to Ang I and activates ERKs, has recently been cloned and is highly expressed in brain. It is, therefore, possible that the renin receptor may enhance the formation of Ang I at selective neuronal sites within the central nervous system. As stated above, because of the low levels of renin in most sites in the brain, the role of a local RAS in mediating physiologic or pathophysiologic effects is uncertain. Furthermore, as

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