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

doi:10.1073/pnas.1432869100

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

^*Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, 31270, Minas Gerais, Brazil; ^†Department of Medicine, Georgetown University, Washington, DC 20057; ^‡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

Edited by Richard P. Lifton, Yale University School of Medicine, New Haven, CT (received for review 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.

Footnotes

↵ ** 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}ukbf.fu-berlin.de.
↵ ∥ Present address: Department of Pharmacology, School of Pharmacy, University of Mississippi, University, MS 38677-1848.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: Ang, angiotensin; AVP, arginine-vasopressin; AA, arachidonic acid; CHO, Chinese hamster ovary.