The Renin–Angiotensin–Aldosterone System (RAAS): Beyond Cardiovascular Regulation
Simple Summary
Abstract
1. Introduction
2. Recent Advances in Renin–Angiotensin System Research
3. Species Differences in RAAS and Their Physiological and Pathological Impacts
4. Functional Axes and Balance
5. Localization and Binding Specificity of AT2 and Mas Receptors
6. Selective Regulation of ACE/Ang II/AT1R and ACE2/Ang 1–7/Mas Receptor Pathways
6.1. ACE/Angiotensin II/AT1 Receptor Pathway (Classical Axis)
6.2. ACE2/Angiotensin-(1-7)/Mas Receptor and AT2 Receptor Pathway (Protective Axis)
6.3. Mechanisms Maintaining Balance
6.4. Genetic and Epigenetic Regulation
7. Tissue-Specific Roles of Angiotensin II and Local RAS Autonomy
7.1. Central Nervous System (CNS)
7.2. Immune System
7.3. Metabolic Tissues
7.4. Cardiovascular System
7.5. Kidney
8. Clinical Evidence and Benefits of AT1R/Ang II Inhibitors
9. AT1R and AT2R: Opposing Effects
10. Intracellular and Mitochondrial Effects of Ang II
11. Caveolae and AT1R Signaling
12. Nuclear Effects and Fibrosis
13. Tissue-Specific Roles and Gene Knockouts
14. Role of RAAS in Hepatic Fibrosis Development
15. Inflammation, Immunomodulation, and Related Disorders
16. RAAS and Cancer
17. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
Abbreviations
RAAS | renin–angiotensin–aldosterone system |
ACE | angiotensin-converting enzyme system |
ANG | Angiotensinogen |
AKT | Protein kinase B |
APA | Aminopeptidase A |
ATR | Angiotensin receptor |
ADH | Antidiuretic hormone |
MASR | MAS receptor |
ERK | extracellular signal-regulated kinase |
PI3K | phosphoinositide 3-kinase |
NO | Nitric oxide |
COX-2 | cyclo-oxygenase-2 |
FOXO1 | forkhead box O1 |
ROS | reactive oxygen species |
VSMC | vascular smooth muscle cell |
MrgD | Mas-related G protein-coupled receptor D |
HDAC | histone deacetylase |
sGC | soluble guanylate cyclase |
MAPK | Mitogen-activated protein kinases |
SHP-1 | src homology region 2 domain-containing phosphatase-1 |
NICD | intracellular Notch domain |
AAA | aorto-abdominal |
TAA | thoracic aneurysm |
iNOS | inducible oxide nitric sinthase, inducible nitric oxide synthase |
eNOS | endothelial nitric oxide synthase |
References
- de Miranda, F.S.; Guimarães, J.P.T.; Menikdiwela, K.R.; Mabry, B.; Dhakal, R.; layeequr Rahman, R.; Moussa, H.; Moustaid-Moussa, N. Breast Cancer and the Renin-Angiotensin System (RAS): Therapeutic Approaches and Related Metabolic Diseases. Mol. Cell. Endocrinol. 2021, 528, 111245. [Google Scholar] [CrossRef]
- Kobori, H.; Nangaku, M.; Navar, L.G.; Nishiyama, A. The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney Disease. Pharmacol. Rev. 2007, 59, 251–287. [Google Scholar] [CrossRef] [PubMed]
- Lavoie, J.L.; Sigmund, C.D. Minireview: Overview of the Renin-Angiotensin System—An Endocrine and Paracrine System. Endocrinology 2003, 144, 2179–2183. [Google Scholar] [CrossRef] [PubMed]
- Re, R.N. Cellular Biology of the Renin-Angiotensin Systems. Arch. Intern. Med. 1984, 144, 2037–2041. [Google Scholar] [CrossRef] [PubMed]
- Turner, A.J.; Hooper, N.M. The Angiotensin–Converting Enzyme Gene Family: Genomics and Pharmacology. Trends Pharmacol. Sci. 2002, 23, 177–183. [Google Scholar] [CrossRef] [PubMed]
- Rice, G.I.; Thomas, D.A.; Grant, P.J.; Turner, A.J.; Hooper, N.M. Evaluation of Angiotensin-Converting Enzyme (ACE), Its Homologue ACE2 and Neprilysin in Angiotensin Peptide Metabolism. Biochem. J. 2004, 383, 45–51. [Google Scholar] [CrossRef] [PubMed]
- Passos-Silva, D.G.; Verano-Braga, T.; Santos, R.A. Angiotensin-(1–7): Beyond the Cardio-Renal Actions. Clin. Sci. 2013, 124, 443–456. [Google Scholar] [CrossRef]
- Ferrario, C.M.; Iyer, S.N. Angiotensin-(1–7): A Bioactive Fragment of the Renin–Angiotensin System. Regul. Pept. 1998, 78, 13–18. [Google Scholar] [CrossRef]
- Yugandhar, V.G.; Clark, M.A. Angiotensin III: A Physiological Relevant Peptide of the Renin Angiotensin System. Peptides 2013, 46, 26–32. [Google Scholar] [CrossRef]
- Ferrario, C.M.; Chappell, M.C. What’s New in the Renin-Angiotensin System? Cell. Mol. Life Sci. 2004, 61, 2720. [Google Scholar] [CrossRef]
- Jankowski, V.; Vanholder, R.; Van Der Giet, M.; Tölle, M.; Karadogan, S.; Gobom, J.; Furkert, J.; Oksche, A.; Krause, E.; Anh Tran, T.N.; et al. Mass-Spectrometric Identification of a Novel Angiotensin Peptide in Human Plasma. Arter. Thromb. Vasc. Biol. 2007, 27, 297–302. [Google Scholar] [CrossRef]
- Lautner, R.Q.; Villela, D.C.; Fraga-Silva, R.A.; Silva, N.; Verano-Braga, T.; Costa-Fraga, F.; Jankowski, J.; Jankowski, V.; Sousa, F.; Alzamora, A.; et al. Discovery and Characterization of Alamandine: A Novel Component of the Renin–Angiotensin System. Circ. Res. 2013, 112, 1104–1111. [Google Scholar] [CrossRef]
- Hrenak, J.; Paulis, L.; Simko, F. Angiotensin A/Alamandine/MrgD Axis: Another Clue to Understanding Cardiovascular Pathophysiology. Int. J. Mol. Sci. 2016, 17, 1098. [Google Scholar] [CrossRef] [PubMed]
- Vargas, R.A.V.; Millán, J.M.V.; Bonilla, E.F. Renin–Angiotensin System: Basic and Clinical Aspects—A General Perspective. Endocrinol. Diabetes Nutr. (Engl. Ed.) 2022, 69, 52–62. [Google Scholar]
- Bader, M.; Steckelings, U.M.; Alenina, N.; Santos, R.A.S.; Ferrario, C.M. Alternative Renin-Angiotensin System. Hypertension 2024, 81, 964–976. [Google Scholar] [CrossRef]
- Karimi, F.; Maleki, M.; Movahedpour, A.; Alizadeh, M.; Kharazinejad, E.; Sabaghan, M. Overview of the Renin-Angiotensin System in Diabetic Nephropathy. J. Renin Angiotensin Aldosterone Syst. 2024, 25, 14703203241302966. [Google Scholar] [CrossRef]
- Rodríguez-Pallares, J.; Garcia-Crivaro, L.A.; Parga, J.A.; Labandeira-Garcia, J.L. Renin-Angiotensin System as an Emerging Target to Modulate Adult Neurogenesis in Health and Disease. Stem Cell Res. Ther. 2025, 16, 332. [Google Scholar] [CrossRef]
- Ruan, Y.; Yu, Y.; Wu, M.; Jiang, Y.; Qiu, Y.; Ruan, S. The Renin-Angiotensin-Aldosterone System: An Old Tree Sprouts New Shoots. Cell. Signal. 2024, 124, 111426. [Google Scholar] [CrossRef]
- Fountain, J.H.; Kaur, J.; Lappin, S.L. Physiology, Renin Angiotensin System. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2025. [Google Scholar]
- Carey, R.M.; Siragy, H.M. The Intrarenal Renin–Angiotensin System and Diabetic Nephropathy. Trends Endocrinol. Metab. 2003, 14, 274–281. [Google Scholar] [CrossRef]
- Peach, M.J. Renin-Angiotensin System: Biochemistry and Mechanisms of Action. Physiol. Rev. 1977, 57, 313–370. [Google Scholar] [CrossRef]
- Balcells, E.; Meng, Q.C.; Johnson, W.H.; Oparil, S.; Dell’Italia, L.J. Angiotensin II Formation from ACE and Chymase in Human and Animal Hearts: Methods and Species Considerations. Am. J. Physiol.-Heart Circ. Physiol. 1997, 273, H1769–H1774. [Google Scholar] [CrossRef] [PubMed]
- Kato, H.; Ishida, J.; Nagano, K.; Honjo, K.; Sugaya, T.; Takeda, N.; Sugiyama, F.; Yagami, K.; Fujita, T.; Nangaku, M. Deterioration of Atherosclerosis in Mice Lacking Angiotensin II Type 1A Receptor in Bone Marrow-Derived Cells. Lab. Investig. 2008, 88, 731–739. [Google Scholar] [CrossRef] [PubMed]
- Pfaff, D.W.; Rubin, R.T.; Schneider, J.E.; Head, G. Principles of Hormone/Behavior Relations; Academic Press: Cambridge, MA, USA, 2018; ISBN 978-0-12-802667-0. [Google Scholar]
- Steckelings, U.M.; Widdop, R.E.; Sturrock, E.D.; Lubbe, L.; Hussain, T.; Kaschina, E.; Unger, T.; Hallberg, A.; Carey, R.M.; Sumners, C. The Angiotensin AT2 Receptor: From a Binding Site to a Novel Therapeutic Target. Pharmacol. Rev. 2022, 74, 1051–1135. [Google Scholar] [CrossRef] [PubMed]
- Ferrario, C.M.; Chappell, M.C. Novel Angiotensin Peptides. Cell Mol. Life Sci. 2004, 61, 2720–2727. [Google Scholar] [CrossRef]
- Santos, R.A.S.; Oudit, G.Y.; Verano-Braga, T.; Canta, G.; Steckelings, U.M.; Bader, M. The Renin-Angiotensin System: Going beyond the Classical Paradigms. Am. J. Physiol.-Heart Circ. Physiol. 2019, 316, H958–H970. [Google Scholar] [CrossRef]
- Takai, S.; Jin, D.; Sakaguchi, M.; Miyazaki, M. Chymase-Dependent Angiotensin II Formation in Human Vascular Tissue. Circulation 1999, 100, 654–658. [Google Scholar] [CrossRef]
- Hollenberg, N.K. Implications of Species Difference for Clinical Investigation: Studies on the Renin-Angiotensin System. Hypertension 2000, 35, 150–154. [Google Scholar] [CrossRef]
- Rabelo, L.A.; Alenina, N.; Bader, M. ACE2–Angiotensin-(1–7)–Mas Axis and Oxidative Stress in Cardiovascular Disease. Hypertens. Res. 2011, 34, 154–160. [Google Scholar] [CrossRef]
- Tikellis, C.; Thomas, M.C. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease. Int. J. Pept. 2012, 2012, 1–8. [Google Scholar] [CrossRef]
- Iwata, M.; Cowling, R.T.; Yeo, S.J.; Greenberg, B. Targeting the ACE2–Ang-(1–7) Pathway in Cardiac Fibroblasts to Treat Cardiac Remodeling and Heart Failure. J. Mol. Cell. Cardiol. 2011, 51, 542–547. [Google Scholar] [CrossRef]
- Qaradakhi, T.; Apostolopoulos, V.; Zulli, A. Angiotensin (1-7) and Alamandine: Similarities and Differences. Pharmacol. Res. 2016, 111, 820–826. [Google Scholar] [CrossRef] [PubMed]
- Alenina, N.; Xu, P.; Rentzsch, B.; Patkin, E.L.; Bader, M. Genetically Altered Animal Models for Mas and Angiotensin-(1–7). Exp. Physiol. 2008, 93, 528–537. [Google Scholar] [CrossRef] [PubMed]
- Porrello, E.R.; Delbridge, L.M.D.; Thomas, W.G. The Angiotensin II Type 2 (AT2) Receptor: An Enigmatic Seven Transmembrane Receptor. Front. Biosci. (Landmark Ed.) 2009, 14, 958–972. [Google Scholar] [CrossRef]
- Carey, R.M. AT2 Receptors: Potential Therapeutic Targets for Hypertension. Am. J. Hypertens. 2017, 30, 339–347. [Google Scholar] [CrossRef]
- Matavelli, L.C.; Siragy, H.M. AT2 Receptor Activities and Pathophysiological Implications. J. Cardiovasc. Pharmacol. 2015, 65, 226–232. [Google Scholar] [CrossRef]
- Jones, E.S.; Vinh, A.; McCarthy, C.A.; Gaspari, T.A.; Widdop, R.E. AT2 Receptors: Functional Relevance in Cardiovascular Disease. Pharmacol. Ther. 2008, 120, 292–316. [Google Scholar] [CrossRef]
- Sampaio, W.O.; Souza Dos Santos, R.A.; Faria-Silva, R.; Da Mata Machado, L.T.; Schiffrin, E.L.; Touyz, R.M. Angiotensin-(1-7) Through Receptor Mas Mediates Endothelial Nitric Oxide Synthase Activation via Akt-Dependent Pathways. Hypertension 2007, 49, 185–192. [Google Scholar] [CrossRef]
- Santos, R.A.S.; E Silva, A.C.S.; Maric, C.; Silva, D.M.R.; Machado, R.P.; De Buhr, I.; Heringer-Walther, S.; Pinheiro, S.V.B.; Lopes, M.T.; Bader, M.; et al. Angiotensin-(1–7) Is an Endogenous Ligand for the G Protein-Coupled Receptor Mas. Proc. Natl. Acad. Sci. USA 2003, 100, 8258–8263. [Google Scholar] [CrossRef]
- Tallant, E.A.; Ferrario, C.M.; Gallagher, P.E. Angiotensin-(1–7) Inhibits Growth of Cardiac Myocytes through Activation of the Mas. Receptor. Am. J. Physiol.-Heart Circ. Physiol. 2005, 289, H1560–H1566. [Google Scholar] [CrossRef]
- Hammer, A.; Yang, G.; Friedrich, J.; Kovacs, A.; Lee, D.-H.; Grave, K.; Jörg, S.; Alenina, N.; Grosch, J.; Winkler, J.; et al. Role of the Receptor Mas in Macrophage-Mediated Inflammation in Vivo. Proc. Natl. Acad. Sci. USA 2016, 113, 14109–14114. [Google Scholar] [CrossRef]
- Santos, R.A.S.; Sampaio, W.O.; Alzamora, A.C.; Motta-Santos, D.; Alenina, N.; Bader, M.; Campagnole-Santos, M.J. The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7). Physiol. Rev. 2018, 98, 505–553. [Google Scholar] [CrossRef]
- Xu, P.; Costa-Goncalves, A.C.; Todiras, M.; Rabelo, L.A.; Sampaio, W.O.; Moura, M.M.; Sousa Santos, S.; Luft, F.C.; Bader, M.; Gross, V.; et al. Endothelial Dysfunction and Elevated Blood Pressure in Mas. Gene-Deleted Mice. Hypertension 2008, 51, 574–580. [Google Scholar] [CrossRef]
- Sarzani, R.; Giulietti, F.; Di Pentima, C.; Giordano, P.; Spannella, F. Disequilibrium between the Classic Renin-Angiotensin System and Its Opposing Arm in SARS-CoV-2-Related Lung Injury. Am. J. Physiol. Lung Cell Mol. Physiol. 2020, 319, L325–L336. [Google Scholar] [CrossRef] [PubMed]
- Gheblawi, M.; Wang, K.; Viveiros, A.; Nguyen, Q.; Zhong, J.-C.; Turner, A.J.; Raizada, M.K.; Grant, M.B.; Oudit, G.Y. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2. Circ. Res. 2020, 126, 1456–1474. [Google Scholar] [CrossRef] [PubMed]
- Patel, V.B.; Zhong, J.-C.; Grant, M.B.; Oudit, G.Y. Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure. Circ. Res. 2016, 118, 1313–1326. [Google Scholar] [CrossRef] [PubMed]
- Grobe, J.L.; Mecca, A.P.; Lingis, M.; Shenoy, V.; Bolton, T.A.; Machado, J.M.; Speth, R.C.; Raizada, M.K.; Katovich, M.J. Prevention of Angiotensin II-Induced Cardiac Remodeling by Angiotensin-(1–7). Am. J. Physiol.-Heart Circ. Physiol. 2007, 292, H736–H742. [Google Scholar] [CrossRef]
- Engeli, S.; Schling, P.; Gorzelniak, K.; Boschmann, M.; Janke, J.; Ailhaud, G.; Teboul, M.; Massiéra, F.; Sharma, A.M. The Adipose-Tissue Renin-Angiotensin-Aldosterone System: Role in the Metabolic Syndrome? Int. J. Biochem. Cell Biol. 2003, 35, 807–825. [Google Scholar] [CrossRef]
- McGrath, M.S.; Wentworth, B.J. The Renin–Angiotensin System in Liver Disease. Int. J. Mol. Sci. 2024, 25, 5807. [Google Scholar] [CrossRef]
- Bayraktutan, U. Angiotensin II and Cardiovascular Disease: Balancing Pathogenic and Protective Pathways. Curr. Issues Mol. Biol. 2025, 47, 501. [Google Scholar] [CrossRef]
- Crowley, S.D.; Rudemiller, N.P. Immunologic Effects of the Renin-Angiotensin System. J. Am. Soc. Nephrol. 2017, 28, 1350–1361. [Google Scholar] [CrossRef]
- Sandberg, K.; Ji, H. Kidney Angiotensin Receptors and Their Role in Renal Pathophysiology. Semin. Nephrol. 2000, 20, 402–416. [Google Scholar]
- Sobhy, M.; Eletriby, A.; Ragy, H.; Kandil, H.; Saleh, M.A.; Farag, N.; Guindy, R.; Bendary, A.; Nayel, A.M.E.; Shawky, A.; et al. ACE Inhibitors and Angiotensin Receptor Blockers for the Primary and Secondary Prevention of Cardiovascular Outcomes: Recommendations from the 2024 Egyptian Cardiology Expert Consensus in Collaboration with the CVREP Foundation. Cardiol. Ther. 2024, 13, 707–736. [Google Scholar] [CrossRef]
- Balogh, M.; Aguilar, C.; Nguyen, N.T.; Shepherd, A.J. Angiotensin Receptors and Neuropathic Pain. Pain Rep. 2021, 6, e869. [Google Scholar] [CrossRef]
- Fatima, N.; Patel, S.N.; Hussain, T. Angiotensin II Type 2 Receptor: A Target for Protection Against Hypertension, Metabolic Dysfunction, and Organ Remodeling. Hypertension 2021, 77, 1845–1856. [Google Scholar] [CrossRef] [PubMed]
- Eklind-Cervenka, M.; Benson, L.; Dahlström, U.; Edner, M.; Rosenqvist, M.; Lund, L.H. Association of Candesartan vs Losartan with All-Cause Mortality in Patients with Heart Failure. JAMA 2011, 305, 175–182. [Google Scholar] [CrossRef] [PubMed]
- Shanmugam, P.; Valente, A.J.; Prabhu, S.D.; Venkatesan, B.; Yoshida, T.; Delafontaine, P.; Chandrasekar, B. Angiotensin-II Type 1 Receptor and NOX2 Mediate TCF/LEF and CREB Dependent WISP1 Induction and Cardiomyocyte Hypertrophy. J. Mol. Cell. Cardiol. 2011, 50, 928–938. [Google Scholar] [CrossRef] [PubMed]
- Guo, Y.; Huang, X.; Liao, W.; Meng, L.; Xu, D.; Ye, C.; Chen, L.; Hu, T. Discovery and Optimization of Highly Potent and Selective AT2R Antagonists to Relieve Peripheral Neuropathic Pain. ACS Omega 2021, 6, 15412–15420. [Google Scholar] [CrossRef]
- Pulakat, L.; Sumners, C. Angiotensin Type 2 Receptors: Painful, or Not? Front. Pharmacol. 2020, 11, 571994. [Google Scholar] [CrossRef]
- Sabnis, R.W. Novel AT2R Antagonists for Treating Chronic Pain. ACS Med. Chem. Lett. 2024, 15, 326–327. [Google Scholar] [CrossRef]
- Kambayashi, Y.; Bardhan, S.; Takahashi, K.; Tsuzuki, S.; Inui, H.; Hamakubo, T.; Inagami, T. Molecular Cloning of a Novel Angiotensin II Receptor Isoform Involved in Phosphotyrosine Phosphatase Inhibition. J. Biol. Chem. 1993, 268, 24543–24546. [Google Scholar] [CrossRef]
- Mukoyama, M.; Nakajima, M.; Horiuchi, M.; Sasamura, H.; Pratt, R.E.; Dzau, V.J. Expression Cloning of Type 2 Angiotensin II Receptor Reveals a Unique Class of Seven-Transmembrane Receptors. J. Biol. Chem. 1993, 268, 24539–24542. [Google Scholar] [CrossRef]
- Carey, R.M. Cardiovascular and Renal Regulation by the Angiotensin Type 2 Receptor: The AT2 Receptor Comes of Age. Hypertension 2005, 45, 840–844. [Google Scholar] [CrossRef] [PubMed]
- Reudelhuber, T.L. The Continuing Saga of the AT2 Receptor: A Case of the Good, the Bad, and the Innocuous. Hypertension 2005, 46, 1261–1262. [Google Scholar] [CrossRef] [PubMed]
- Villela, D.C.; Passos-Silva, D.G.; Santos, R.A. Alamandine: A New Member of the Angiotensin Family. Curr. Opin. Nephrol. Hypertens. 2014, 23, 130–134. [Google Scholar] [CrossRef] [PubMed]
- Coble, J.P.; Grobe, J.L.; Johnson, A.K.; Sigmund, C.D. Mechanisms of Brain Renin Angiotensin System-Induced Drinking and Blood Pressure: Importance of the Subfornical Organ. Am. J. Physiol.-Regul. Integr. Comp. Physiol. 2015, 308, R238–R249. [Google Scholar] [CrossRef]
- Satou, R.; Shao, W.; Navar, L.G. Role of Stimulated Intrarenal Angiotensinogen in Hypertension. Ther. Adv. Cardiovasc. Dis. 2015, 9, 181–190. [Google Scholar] [CrossRef]
- Gibbons, G.H.; Pratt, R.; Dzau, V.J. Vascular Smooth Muscle Cell Hypertrophy vs. Hyperplasia. Autocrine Transforming Growth Factor-Beta 1 Expression Determines Growth Response to Angiotensin II. J. Clin. Investig. 1992, 90, 456–461. [Google Scholar] [CrossRef]
- Sadoshima, J.; Izumo, S. Molecular Characterization of Angiotensin II--Induced Hypertrophy of Cardiac Myocytes and Hyperplasia of Cardiac Fibroblasts. Critical Role of the AT1 Receptor Subtype. Circ. Res. 1993, 73, 413–423. [Google Scholar] [CrossRef]
- Cheng, N.; Bai, X.; Shu, Y.; Ahmad, O.; Shen, P. Targeting Tumor-Associated Macrophages as an Antitumor Strategy. Biochem. Pharmacol. 2021, 183, 114354. [Google Scholar] [CrossRef]
- Salgado, R.; Denkert, C.; Demaria, S.; Sirtaine, N.; Klauschen, F.; Pruneri, G.; Wienert, S.; Van den Eynden, G.; Baehner, F.L.; Pénault-Llorca, F. The Evaluation of Tumor-Infiltrating Lymphocytes (TILs) in Breast Cancer: Recommendations by an International TILs Working Group 2014. Ann. Oncol. 2015, 26, 259–271. [Google Scholar] [CrossRef]
- Zhang, Q.; Lu, S.; Li, T.; Yu, L.; Zhang, Y.; Zeng, H.; Qian, X.; Bi, J.; Lin, Y. ACE2 Inhibits Breast Cancer Angiogenesis via Suppressing the VEGFa/VEGFR2/ERK Pathway. J. Exp. Clin. Cancer Res. 2019, 38, 173. [Google Scholar] [CrossRef]
- Forrester, S.J.; Booz, G.W.; Sigmund, C.D.; Coffman, T.M.; Kawai, T.; Rizzo, V.; Scalia, R.; Eguchi, S. Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology. Physiol. Rev. 2018, 98, 1627–1738. [Google Scholar] [CrossRef] [PubMed]
- Takayanagi, T.; Bourne, A.M.; Kimura, K.; Takaguri, A.; Elliott, K.J.; Eguchi, K.; Eguchi, S. Constitutive Stimulation of Vascular Smooth Muscle Cells by Angiotensin II Derived from an Adenovirus Encoding a Furin-Cleavable Fusion Protein. Am. J. Hypertens. 2012, 25, 280–283. [Google Scholar] [CrossRef] [PubMed]
- Dikalov, S.I.; Nazarewicz, R.R.; Bikineyeva, A.; Hilenski, L.; Lassègue, B.; Griendling, K.K.; Harrison, D.G.; Dikalova, A.E. Nox2-Induced Production of Mitochondrial Superoxide in Angiotensin II-Mediated Endothelial Oxidative Stress and Hypertension. Antioxid. Redox Signal. 2014, 20, 281–294. [Google Scholar] [CrossRef]
- Owens, A.P.; Subramanian, V.; Moorleghen, J.J.; Guo, Z.; McNamara, C.A.; Cassis, L.A.; Daugherty, A. Angiotensin II Induces a Region-Specific Hyperplasia of the Ascending Aorta Through Regulation of Inhibitor of Differentiation 3. Circ. Res. 2010, 106, 611–619. [Google Scholar] [CrossRef]
- Ozasa, Y.; Akazawa, H.; Qin, Y.; Tateno, K.; Ito, K.; Kudo-Sakamoto, Y.; Yano, M.; Yabumoto, C.; Naito, A.T.; Oka, T. Notch Activation Mediates Angiotensin II-Induced Vascular Remodeling by Promoting the Proliferation and Migration of Vascular Smooth Muscle Cells. Hypertens. Res. 2013, 36, 859–865. [Google Scholar] [CrossRef]
- MacDonald, B.T.; Tamai, K.; He, X. Wnt/β-Catenin Signaling: Components, Mechanisms, and Diseases. Dev. Cell 2009, 17, 9–26. [Google Scholar] [CrossRef]
- Campos, A.H.; Wang, W.; Pollman, M.J.; Gibbons, G.H. Determinants of Notch-3 Receptor Expression and Signaling in Vascular Smooth Muscle Cells: Implications in Cell-Cycle Regulation. Circ. Res. 2002, 91, 999–1006. [Google Scholar] [CrossRef]
- Qi, X.; Disatnik, M.-H.; Shen, N.; Sobel, R.A.; Mochly-Rosen, D. Aberrant Mitochondrial Fission in Neurons Induced by Protein Kinase Cδ under Oxidative Stress Conditions in Vivo. Mol. Biol. Cell 2011, 22, 256–265. [Google Scholar] [CrossRef]
- Lim, S.; Lee, S.; Seo, H.; Ham, O.; Lee, C.; Park, J.; Lee, J.; Seung, M.; Yun, I.; Han, S.M.; et al. Regulation of Mitochondrial Morphology by Positive Feedback Interaction Between PKCδ and Drp1 in Vascular Smooth Muscle Cell. J. Cell. Biochem. 2015, 116, 648–660. [Google Scholar] [CrossRef]
- Ishizaka, N.; Griendling, K.K.; Lassègue, B.; Alexander, R.W. Angiotensin II Type 1 Receptor: Relationship with Caveolae and Caveolin After Initial Agonist Stimulation. Hypertension 1998, 32, 459–466. [Google Scholar] [CrossRef] [PubMed]
- Leclerc, P.C.; Auger-Messier, M.; Lanctot, P.M.; Escher, E.; Leduc, R.; Guillemette, G. A Polyaromatic Caveolin-Binding-like Motif in the Cytoplasmic Tail of the Type 1 Receptor for Angiotensin II Plays an Important Role in Receptor Trafficking and Signaling. Endocrinology 2002, 143, 4702–4710. [Google Scholar] [CrossRef] [PubMed]
- Li, X.C.; Gu, V.; Miguel-Qin, E.; Zhuo, J.L. Role of Caveolin 1 in AT1a Receptor-Mediated Uptake of Angiotensin II in the Proximal Tubule of the Kidney. Am. J. Physiol.-Ren. Physiol. 2014, 307, F949–F961. [Google Scholar] [CrossRef] [PubMed]
- Linder, A.E.; Thakali, K.M.; Thompson, J.M.; Watts, S.W.; Webb, R.C.; Leite, R. Methyl-β-Cyclodextrin Prevents Angiotensin II-Induced Tachyphylactic Contractile Responses in Rat Aorta. J. Pharmacol. Exp. Ther. 2007, 323, 78–84. [Google Scholar] [CrossRef]
- Tadevosyan, A.; Létourneau, M.; Folch, B.; Doucet, N.; Villeneuve, L.R.; Mamarbachi, A.M.; Pétrin, D.; Hébert, T.E.; Fournier, A.; Chatenet, D.; et al. Photoreleasable Ligands to Study Intracrine Angiotensin II Signalling. J. Physiol. 2015, 593, 521–539. [Google Scholar] [CrossRef]
- Choi, H.; Allahdadi, K.J.; Tostes, R.C.; Webb, R.C. Augmented S-Nitrosylation Contributes to Impaired Relaxation in Angiotensin II Hypertensive Mouse Aorta: Role of Thioredoxin Reductase. J. Hypertens. 2011, 29, 2359–2368. [Google Scholar] [CrossRef]
- Crassous, P.-A.; Couloubaly, S.; Huang, C.; Zhou, Z.; Baskaran, P.; Kim, D.D.; Papapetropoulos, A.; Fioramonti, X.; Durán, W.N.; Beuve, A. Soluble Guanylyl Cyclase Is a Target of Angiotensin II-Induced Nitrosative Stress in a Hypertensive Rat Model. Am. J. Physiol.-Heart Circ. Physiol. 2012, 303, H597–H604. [Google Scholar] [CrossRef]
- George, A.J.; Purdue, B.W.; Gould, C.M.; Thomas, D.W.; Handoko, Y.; Qian, H.; Quaife-Ryan, G.A.; Morgan, K.A.; Simpson, K.J.; Thomas, W.G. A Functional siRNA Screen Identifies Genes Modulating Angiotensin II-Mediated EGFR Transactivation. J. Cell Sci. 2013, 126, 5377–5390. [Google Scholar] [CrossRef]
- Makhanova, N.A.; Crowley, S.D.; Griffiths, R.C.; Coffman, T.M. Gene Expression Profiles Linked to AT1 Angiotensin Receptors in the Kidney. Physiol. Genom. 2010, 42A, 211–218. [Google Scholar] [CrossRef]
- Rateri, D.L.; Moorleghen, J.J.; Balakrishnan, A.; Owens, A.P.; Howatt, D.A.; Subramanian, V.; Poduri, A.; Charnigo, R.; Cassis, L.A.; Daugherty, A. Endothelial Cell–Specific Deficiency of Ang II Type 1a Receptors Attenuates Ang II–Induced Ascending Aortic Aneurysms in LDL Receptor−/− Mice. Circ. Res. 2011, 108, 574–581. [Google Scholar] [CrossRef]
- Rateri, D.L.; Moorleghen, J.J.; Knight, V.; Balakrishnan, A.; Howatt, D.A.; Cassis, L.A.; Daugherty, A. Depletion of Endothelial or Smooth Muscle Cell-Specific Angiotensin II Type 1a Receptors Does Not Influence Aortic Aneurysms or Atherosclerosis in LDL Receptor Deficient Mice. PLoS ONE 2012, 7, e51483. [Google Scholar] [CrossRef] [PubMed]
- Wu, Y.; Yin, A.-H.; Sun, J.-T.; Xu, W.-H.; Zhang, C.-Q. Angiotensin-Converting Enzyme 2 Improves Liver Fibrosis in Mice by Regulating Autophagy of Hepatic Stellate Cells. World J. Gastroenterol. 2023, 29, 4975. [Google Scholar] [CrossRef] [PubMed]
- Zhao, B.-W.; Chen, Y.-J.; Zhang, R.-P.; Chen, Y.-M.; Huang, B.-W. Angiotensin-Converting Enzyme 2 Alleviates Liver Fibrosis through the Renin-Angiotensin System. World J. Gastroenterol. 2024, 30, 607. [Google Scholar] [CrossRef] [PubMed]
- Osterreicher, C.H.; Taura, K.; De Minicis, S.; Seki, E.; Penz-Osterreicher, M.; Kodama, Y.; Kluwe, J.; Schuster, M.; Oudit, G.Y.; Penninger, J.M.; et al. Angiotensin-Converting-Enzyme 2 Inhibits Liver Fibrosis in Mice. Hepatology 2009, 50, 929–938. [Google Scholar] [CrossRef]
- Li, S.; Zhao, W.; Tao, Y.; Liu, C. Fugan Wan Alleviates Hepatic Fibrosis by Inhibiting ACE/Ang II/AT-1R Signaling Pathway and Enhancing ACE2/Ang 1-7/Mas Signaling Pathway in Hepatic Fibrosis Rat Models. Am. J. Transl. Res. 2020, 12, 592. [Google Scholar]
- Nguyen, G. Renin,(pro) Renin and Receptor: An Update. Clin. Sci. 2011, 120, 169–178. [Google Scholar] [CrossRef]
- Padia, S.H.; Carey, R.M. AT 2 Receptors: Beneficial Counter-Regulatory Role in Cardiovascular and Renal Function. Pflügers Arch.-Eur. J. Physiol. 2013, 465, 99–110. [Google Scholar] [CrossRef]
- Sumners, C.; de Kloet, A.D.; Krause, E.G.; Unger, T.; Steckelings, U.M. Angiotensin Type 2 Receptors: Blood Pressure Regulation and End Organ Damage. Curr. Opin. Pharmacol. 2015, 21, 115–121. [Google Scholar] [CrossRef]
- Berk, B.C. Angiotensin Type 2 Receptor (AT2R): A Challenging Twin. Sci. STKE 2003, 2003, pe16. [Google Scholar] [CrossRef]
- Blodow, S.; Schneider, H.; Storch, U.; Wizemann, R.; Forst, A.-L.; Gudermann, T.; Mederos y Schnitzler, M. Novel Role of Mechanosensitive AT 1B Receptors in Myogenic Vasoconstriction. Pflügers Arch.-Eur. J. Physiol. 2014, 466, 1343–1353. [Google Scholar] [CrossRef]
- Kanematsu, Y.; Kanematsu, M.; Kurihara, C.; Tada, Y.; Tsou, T.-L.; Van Rooijen, N.; Lawton, M.T.; Young, W.L.; Liang, E.I.; Nuki, Y.; et al. Critical Roles of Macrophages in the Formation of Intracranial Aneurysm. Stroke 2011, 42, 173–178. [Google Scholar] [CrossRef]
- Kossmann, S.; Hu, H.; Steven, S.; Schönfelder, T.; Fraccarollo, D.; Mikhed, Y.; Brähler, M.; Knorr, M.; Brandt, M.; Karbach, S.H. Inflammatory Monocytes Determine Endothelial Nitric-Oxide Synthase Uncoupling and Nitro-Oxidative Stress Induced by Angiotensin II. J. Biol. Chem. 2014, 289, 27540–27550. [Google Scholar] [CrossRef]
- Zhu, P.; Verma, A.; Prasad, T.; Li, Q. Expression and Function of Mas-Related G Protein-Coupled Receptor D and Its Ligand Alamandine in Retina. Mol. Neurobiol. 2020, 57, 513–527. [Google Scholar] [CrossRef]
- Soltani Hekmat, A.; Javanmardi, K. Alamandine: Potential Protective Effects in SARS-CoV-2 Patients. J. Renin Angiotensin Aldosterone Syst. 2021, 2021, 6824259. [Google Scholar] [CrossRef] [PubMed]
- Nehme, A.; Zouein, F.A.; Deris Zayeri, Z.; Zibara, K. An Update on the Tissue Renin Angiotensin System and Its Role in Physiology and Pathology. J. Cardiovasc. Dev. Dis. 2019, 6, 14. [Google Scholar] [CrossRef] [PubMed]
- Sun, H.; Li, T.; Zhuang, R.; Cai, W.; Zheng, Y. Do Renin–Angiotensin System Inhibitors Influence the Recurrence, Metastasis, and Survival in Cancer Patients?: Evidence from a Meta-Analysis Including 55 Studies. Medicine 2017, 96, e6394. [Google Scholar] [CrossRef] [PubMed]
- Haznedaroglu, I.C.; Malkan, U.Y. Local Bone Marrow Renin-Angiotensin System in the Genesis of Leukemia and Other Malignancies. Eur. Rev. Med. Pharmacol. Sci. 2016, 20, 4089–4111. [Google Scholar]
- Hanif, K.; Bid, H.K.; Konwar, R. Reinventing the ACE Inhibitors: Some Old and New Implications of ACE Inhibition. Hypertens. Res. 2010, 33, 11–21. [Google Scholar] [CrossRef]
- Peng, H.; Sarwar, Z.; Yang, X.-P.; Peterson, E.L.; Xu, J.; Janic, B.; Rhaleb, N.; Carretero, O.A.; Rhaleb, N.-E. Profibrotic Role for Interleukin-4 in Cardiac Remodeling and Dysfunction. Hypertension 2015, 66, 582–589. [Google Scholar] [CrossRef]
- Peng, H.; Yang, X.-P.; Carretero, O.A.; Nakagawa, P.; D’Ambrosio, M.; Leung, P.; Xu, J.; Peterson, E.L.; González, G.E.; Harding, P.; et al. Angiotensin II-Induced Dilated Cardiomyopathy in Balb/c but Not C57BL/6J Mice: T-Helper Lymphocyte 2 and Dilated Cardiomyopathy in Hypertensive Mice. Exp. Physiol. 2011, 96, 756–764. [Google Scholar] [CrossRef]
- Amasheh, S.; Barmeyer, C.; Koch, C.S.; Tavalali, S.; Mankertz, J.; Epple, H.-J.; Gehring, M.M.; Florian, P.; Kroesen, A.-J.; Zeitz, M. Cytokine-Dependent Transcriptional down-Regulation of Epithelial Sodium Channel in Ulcerative Colitis. Gastroenterology 2004, 126, 1711–1720. [Google Scholar] [CrossRef]
- Dengler, F.; Domenig, O.; Kather, S.; Burgener, I.A.; Steiner, J.M.; Heilmann, R.M. Dysregulation of Intestinal Epithelial Electrolyte Transport in Canine Chronic Inflammatory Enteropathy and the Role of the Renin-Angiotensin-Aldosterone-System. Front. Vet. Sci. 2023, 10, 1217839. [Google Scholar] [CrossRef]
- Hume, G.E.; Radford-Smith, G.L. ACE Inhibitors and Angiotensin II Receptor Antagonists in Crohn’s Disease Management. Expert. Rev. Gastroenterol. Hepatol. 2008, 2, 645–651. [Google Scholar] [CrossRef]
- Magalhães, D.; Cabral, J.M.; Soares-da-Silva, P.; Magro, F. Role of Epithelial Ion Transports in Inflammatory Bowel Disease. Am. J. Physiol.-Gastrointest. Liver Physiol. 2016, 310, G460–G476. [Google Scholar] [CrossRef] [PubMed]
- Hassani, B.; Attar, Z.; Firouzabadi, N. The Renin-Angiotensin-Aldosterone System (RAAS) Signaling Pathways and Cancer: Foes versus Allies. Cancer Cell Int. 2023, 23, 254. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Q.; Yu, S.; Lam, M.M.T.; Poon, T.C.W.; Sun, L.; Jiao, Y.; Wong, A.S.T.; Lee, L.T.O. Angiotensin II Promotes Ovarian Cancer Spheroid Formation and Metastasis by Upregulation of Lipid Desaturation and Suppression of Endoplasmic Reticulum Stress. J. Exp. Clin. Cancer Res. 2019, 38, 116. [Google Scholar] [CrossRef] [PubMed]
- Ino, K.; Shibata, K.; Kajiyama, H.; Yamamoto, E.; Nagasaka, T.; Nawa, A.; Nomura, S.; Kikkawa, F. Angiotensin II Type 1 Receptor Expression in Ovarian Cancer and Its Correlation with Tumour Angiogenesis and Patient Survival. Br. J. Cancer 2006, 94, 552–560. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Valentini, A.; Heilmann, R.M.; Kühne, A.; Biagini, L.; De Bellis, D.; Rossi, G. The Renin–Angiotensin–Aldosterone System (RAAS): Beyond Cardiovascular Regulation. Vet. Sci. 2025, 12, 777. https://doi.org/10.3390/vetsci12080777
Valentini A, Heilmann RM, Kühne A, Biagini L, De Bellis D, Rossi G. The Renin–Angiotensin–Aldosterone System (RAAS): Beyond Cardiovascular Regulation. Veterinary Sciences. 2025; 12(8):777. https://doi.org/10.3390/vetsci12080777
Chicago/Turabian StyleValentini, Agnese, Romy M. Heilmann, Anna Kühne, Lucia Biagini, Danilo De Bellis, and Giacomo Rossi. 2025. "The Renin–Angiotensin–Aldosterone System (RAAS): Beyond Cardiovascular Regulation" Veterinary Sciences 12, no. 8: 777. https://doi.org/10.3390/vetsci12080777
APA StyleValentini, A., Heilmann, R. M., Kühne, A., Biagini, L., De Bellis, D., & Rossi, G. (2025). The Renin–Angiotensin–Aldosterone System (RAAS): Beyond Cardiovascular Regulation. Veterinary Sciences, 12(8), 777. https://doi.org/10.3390/vetsci12080777