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Pleiotropic AT₁ Receptor Signaling Pathways Mediating Physiological and Pathogenic Actions of Angiotensin II

Department of Physiology (L.H.), Faculty of Medicine, Semmelweis University, H-1444 Budapest, Hungary; and Endocrinology and Reproduction Research Branch (K.J.C.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4510

Address correspondence and requests for reprints to: Kevin J. Catt, Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, Building 49, Room 6A36, National Institutes of Health, Bethesda, Maryland, 20892-4510. E-mail: cattk{at}mail.nih.gov.

Angiotensin II (Ang II) activates a wide spectrum of signaling responses via the AT₁ receptor (AT₁R) that mediate its physiological control of blood pressure, thirst, and sodium balance and its diverse pathological actions in cardiovascular, renal, and other cell types. Ang II-induced AT₁R activation via G_q/11 stimulates phospholipases A₂, C, and D, and activates inositol trisphosphate/Ca²⁺ signaling, protein kinase C isoforms, and MAPKs, as well as several tyrosine kinases (Pyk2, Src, Tyk2, FAK), scaffold proteins (G protein-coupled receptor kinase-interacting protein 1, p130Cas, paxillin, vinculin), receptor tyrosine kinases, and the nuclear factor-B pathway. The AT₁R also signals via G_i/o and G_11/12 and stimulates G protein-independent signaling pathways, such as ß-arrestin-mediated MAPK activation and the Jak/STAT. Alterations in homo- or heterodimerization of the AT₁R may also contribute to its pathophysiological roles. Many of the deleterious actions of AT₁R activation are initiated by locally generated, rather than circulating, Ang II and are concomitant with the harmful effects of aldosterone in the cardiovascular system. AT₁R-mediated overproduction of reactive oxygen species has potent growth-promoting, proinflammatory, and profibrotic actions by exerting positive feedback effects that amplify its signaling in cardiovascular cells, leukocytes, and monocytes. In addition to its roles in cardiovascular and renal disease, agonist-induced activation of the AT₁R also participates in the development of metabolic diseases and promotes tumor progression and metastasis through its growth-promoting and proangiogenic activities. The recognition of Ang II’s pathogenic actions is leading to novel clinical applications of angiotensin-converting enzyme inhibitors and AT₁R antagonists, in addition to their established therapeutic actions in essential hypertension.

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