Angiotensin-(1-7) Is an Endogenous Ligand for the G Protein-Coupled Receptor Mas

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 14; pp. 8258 - 8263
• Main Authors: Robson A. S. Santos, Ana C. Simoes e Silva, Maric, Christine, Denise M. R. Silva, Machado, Raquel Pillar, de Buhr, Insa, Heringer-Walther, Silvia, Sergio Veloso B. Pinheiro, Lopes, Myriam Teresa, Bader, Michael, Mendes, Elizabeth P., Lemos, Virgina Soares, Campagnole-Santos, Maria Jose, Schultheiss, Heinz-Peter, Speth, Robert, Walther, Thomas
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08-07-2003; National Acad Sciences
• Subjects: Angiotensin I - antagonists & inhibitors; Angiotensin I - pharmacology; Angiotensin I - physiology; Animals; Aorta - drug effects; Arachidonic Acid - secretion; Biological Sciences; Cercopithecus aethiops; CHO Cells; COS Cells; Cricetinae; Cricetulus; Diuresis; Diuresis - drug effects; Hypertension; Kidney - metabolism; Kidneys; Ligands; Mice; Mice, Knockout; Neurotransmitters; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - pharmacology; Peptide Fragments - physiology; Proteins; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - physiology; Receptors; Receptors, G-Protein-Coupled; Recombinant Fusion Proteins - physiology; T tests; Transfection; Urine; Vasodilation - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1432869100

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.