Cardiovascular and Renal Regulation by the Angiotensin Type 2 Receptor

Abstract

The renin-angiotensin system is a coordinated hormonal cascade of major importance in cardiovascular and renal regulation. The principle effector of this system is the octapeptide angiotensin II (Ang II), which acts at 2 cell membrane receptors, AT1 and AT2. The majority of the actions of Ang II have been demonstrated to be mediated by the AT1 receptor, including growth promotion, vasoconstriction, antinatriuresis, aldosterone secretion, salt appetite, thirst, sympathetic outflow and inhibition of renin biosynthesis, and secretion.1 The AT2 receptor has been less well understood. Past studies, however, clearly demonstrated that the AT2 receptor mediates cellular differentiation and growth, opposing the actions of Ang II through the AT1 receptor.2 Studies in the mid to late 1990s demonstrated that AT2 receptor stimulation engenders an autacoid vasodilator cascade composed of bradykinin (BK), nitric oxide (NO), and guanosine cyclic 3′, 5′-monophosphate (cGMP).3–5 This discovery turned attention to the possibility that the AT2 receptor may mediate vasodilation, opposing the vasoconstrictor actions of Ang II at the AT1 receptor.6 Parallel cell signaling studies indicated that the AT2 receptor is G-protein–coupled (through Giα) and that receptor stimulation is accompanied by an increase in phosphotyrosine phosphatase activity and an inhibition of MAP kinase enzymes (p42 and p44) composing the extracellular signal-related kinase (ERK1/2). AT2 receptor-mediated inhibition of the extracellular signal-regulated kinase pathway opposed the actions of Ang II, resulting in extracellular signal-regulated kinase phosphorylation via the AT1 receptor.1,2,6,7 Work during the late 1990s through 2002 suggested that the AT2 receptor might serve as a vasodilator counterforce to the AT1 receptor.2,6,7 However, vasorelaxation was difficult to elicit in some experimental models, attributed to the relatively low level of AT2 receptor vascular expression compared with that of the …