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PNAS 100 (14): 8258-8263

Copyright © 2003 by the National Academy of Sciences.


Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas

Robson A. S. Santos*, Ana C. Simoes e Silva*, Christine Maric{dagger}, Denise M. R. Silva*, Raquel Pillar Machado*, Insa de Buhr{ddagger}, Silvia Heringer-Walther{ddagger}, Sergio Veloso B. Pinheiro*, Myriam Teresa Lopes*, Michael Bader§, Elizabeth P. Mendes*, Virgina Soares Lemos*, Maria Jose Campagnole-Santos*, Heinz-Peter Schultheiss{ddagger}, Robert Speth ,||, and Thomas Walther {ddagger},**

*Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, 31270, Minas Gerais, Brazil; {dagger}Department of Medicine, Georgetown University, Washington, DC 20057; {ddagger}Department of Cardiology and Pneumology, University Hospital Benjamin Franklin, Free University, 12200 Berlin, Germany; §Max Delbrück Center, 13125 Berlin, Germany; and Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, WA 99164-6520

Accepted for publication May 13, 2003.

Received for publication July 30, 2002.

Abstract: The renin–angiotensin system plays a critical role in blood pressure control and body fluid and electrolyte homeostasis. Besides angiotensin (Ang) II, other Ang peptides, such as Ang III [Ang-(2–8)], Ang IV [Ang-(3–8)], and Ang-(1–7) may also have important biological activities. Ang-(1–7) has become an angiotensin of interest in the past few years, because its cardiovascular and baroreflex actions counteract those of Ang II. Unique angiotensin-binding sites specific for this heptapeptide and studies with a selective Ang-(1–7) antagonist indicated the existence of a distinct Ang-(1–7) receptor. We demonstrate that genetic deletion of the G protein-coupled receptor encoded by the Mas protooncogene abolishes the binding of Ang-(1–7) to mouse kidneys. Accordingly, Mas-deficient mice completely lack the antidiuretic action of Ang-(1–7) after an acute water load. Ang-(1–7) binds to Mas-transfected cells and elicits arachidonic acid release. Furthermore, Mas-deficient aortas lose their Ang-(1–7)-induced relaxation response. Collectively, these findings identify Mas as a functional receptor for Ang-(1–7) and provide a clear molecular basis for the physiological actions of this biologically active peptide.

Key Words: binding • Mas protooncogene • renin angiotensin system

** To whom correspondence should be addressed at: Benjamin Franklin Medical Center, Department of Cardiology and Pneumology, Free University of Berlin, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail: thomas.walther{at}

|| Present address: Department of Pharmacology, School of Pharmacy, University of Mississippi, University, MS 38677-1848.

Edited by Richard P. Lifton, Yale University School of Medicine, New Haven, CT

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: Ang, angiotensin; AVP, arginine-vasopressin; AA, arachidonic acid; CHO, Chinese hamster ovary.

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Am J Physiol Heart Circ Physiol 299, H1024-H1033
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Angiotensin (1-7) Receptor Antagonism Equalizes Angiotensin II-Induced Hypertension in Male and Female Spontaneously Hypertensive Rats.
J. C. Sullivan, K. Bhatia, T. Yamamoto, and A. A. Elmarakby (2010)
Hypertension 56, 658-666
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Angiotensin II mediates epithelial-to-mesenchymal transformation in tubular cells by ANG 1-7/MAS-1-dependent pathways.
W. C. Burns, E. Velkoska, R. Dean, L. M. Burrell, and M. C. Thomas (2010)
Am J Physiol Renal Physiol 299, F585-F593
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Vasoprotective and Atheroprotective Effects of Angiotensin (1-7) in Apolipoprotein E-Deficient Mice.
S. Tesanovic, A. Vinh, T. A. Gaspari, D. Casley, and R. E. Widdop (2010)
Arterioscler Thromb Vasc Biol 30, 1606-1613
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Astroglia are a possible cellular substrate of angiotensin(1-7) effects in the rostral ventrolateral medulla.
F. Guo, B. Liu, F. Tang, S. Lane, E. A. Souslova, D. M. Chudakov, J. F. R. Paton, and S. Kasparov (2010)
Cardiovasc Res 87, 578-584
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Angiotensin II signaling through the AT1a and AT1b receptors does not have a role in the development of cerulein-induced chronic pancreatitis in the mouse.
B. Ulmasov, Z. Xu, V. Talkad, K. Oshima, and B. A. Neuschwander-Tetri (2010)
Am J Physiol Gastrointest Liver Physiol 299, G70-G80
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Vascular Relaxation, Antihypertensive Effect, and Cardioprotection of a Novel Peptide Agonist of the Mas Receptor.
S. Q. Savergnini, M. Beiman, R. Q. Lautner, V. de Paula-Carvalho, K. Allahdadi, D. C. Pessoa, F. P. Costa-Fraga, R. A. Fraga-Silva, G. Cojocaru, Y. Cohen, et al. (2010)
Hypertension 56, 112-120
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Inhibition of Angiotensin-Converting Enzyme 2 Exacerbates Cardiac Hypertrophy and Fibrosis in Ren-2 Hypertensive Rats.
A. J. Trask, L. Groban, B. M. Westwood, J. Varagic, D. Ganten, P. E. Gallagher, M. C. Chappell, and C. M. Ferrario (2010)
Am J Hypertens 23, 687-693
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Simultaneous administration of Ang(1-7) or A-779 does not affect the chronic hypertensive effects of angiotensin II in normal rats.
J. P. Collister and D. B. Nahey (2010)
Journal of Renin-Angiotensin-Aldosterone System 11, 99-102
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The ANG-(1-7)/ACE2/mas axis in the regulation of nephron function.
C. M. Ferrario and J. Varagic (2010)
Am J Physiol Renal Physiol 298, F1297-F1305
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Angiotensin-(1-7) stimulates high atrial pacing-induced ANP secretion via Mas/PI3-kinase/Akt axis and Na+/H+ exchanger.
A. Shah, R. Gul, K. Yuan, S. Gao, Y. B. Oh, U. H. Kim, and S. H. Kim (2010)
Am J Physiol Heart Circ Physiol 298, H1365-H1374
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Physiology of Kidney Renin.
H. Castrop, K. Hocherl, A. Kurtz, F. Schweda, V. Todorov, and C. Wagner (2010)
Physiol Rev 90, 607-673
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Lifetime Overproduction of Circulating Angiotensin-(1-7) Attenuates Deoxycorticosterone Acetate-Salt Hypertension-Induced Cardiac Dysfunction and Remodeling.
N. M. Santiago, P. S. Guimaraes, R. A. Sirvente, L. A.M. Oliveira, M. C. Irigoyen, R. A.S. Santos, and M. J. Campagnole-Santos (2010)
Hypertension 55, 889-896
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Circulating Rather Than Cardiac Angiotensin-(1-7) Stimulates Cardioprotection After Myocardial Infarction.
Y. Wang, C. Qian, A. J. M. Roks, D. Westermann, S.-M. Schumacher, F. Escher, R. G. Schoemaker, T. L. Reudelhuber, W. H. van Gilst, H.-P. Schultheiss, et al. (2010)
Circ Heart Fail 3, 286-293
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Infusion of angiotensin-(1-7) reduces glomerulosclerosis through counteracting angiotensin II in experimental glomerulonephritis.
J. Zhang, N. A. Noble, W. A. Border, and Y. Huang (2010)
Am J Physiol Renal Physiol 298, F579-F588
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Expression and Distribution of NADPH Oxidase Isoforms in Human Myometrium--Role in Angiotensin II-induced Hypertrophy.
X.-L. Cui, B. Chang, and L. Myatt (2010)
Biol Reprod 82, 305-312
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Inhibitory effects of angiotensin-(1-7) on the nerve stimulation-induced release of norepinephrine and neuropeptide Y from the mesenteric arterial bed.
M. Byku, H. Macarthur, and T. C. Westfall (2010)
Am J Physiol Heart Circ Physiol 298, H457-H465
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Therapeutic Implications of the Vasoprotective Axis of the Renin-Angiotensin System in Cardiovascular Diseases.
A. J. Ferreira, R. A.S. Santos, C. N. Bradford, A. P. Mecca, C. Sumners, M. J. Katovich, and M. K. Raizada (2010)
Hypertension 55, 207-213
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Effects of Angiotensin Metabolites in the Coronary Vascular Bed of the Spontaneously Hypertensive Rat: Loss of Angiotensin II Type 2 Receptor-Mediated Vasodilation.
E. Moltzer, A. V. A. Verkuil, R. van Veghel, A. H. J. Danser, and J. H. M. van Esch (2010)
Hypertension 55, 516-522
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New Physiological Concepts of the Renin-Angiotensin System From the Investigation of Precursors and Products of Angiotensin I Metabolism.
C. M. Ferrario (2010)
Hypertension 55, 445-452
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Targeting the Degradation of Angiotensin II With Recombinant Angiotensin-Converting Enzyme 2: Prevention of Angiotensin II-Dependent Hypertension.
J. Wysocki, M. Ye, E. Rodriguez, F. R. Gonzalez-Pacheco, C. Barrios, K. Evora, M. Schuster, H. Loibner, K. B. Brosnihan, C. M. Ferrario, et al. (2010)
Hypertension 55, 90-98
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Angiotensin II reduces membranous angiotensin-converting enzyme 2 in pressurized human aortic endothelial cells.
K. Iizuka, A. Kusunoki, T. Machida, and M. Hirafuji (2009)
Journal of Renin-Angiotensin-Aldosterone System 10, 210-215
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