Cardiovascular and Renal Regulation by the Angiotensin Type 2 Receptor

Abstract

T he 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, AT 1 and AT 2 . The majority of the actions of Ang II have been demonstrated to be mediated by the AT 1 receptor, including growth promotion, vasoconstriction, antinatriuresis, aldosterone secretion, salt appetite, thirst, sympathetic outflow and inhibition of renin biosynthesis, and secretion. 1 The AT 2 receptor has been less well understood. Past studies, however, clearly demonstrated that the AT 2 receptor mediates cellular differentiation and growth, opposing the actions of Ang II through the AT 1 receptor. 2 Studies in the mid to late 1990s demonstrated that AT 2 receptor stimulation engenders an autacoid vasodilator cascade composed of bradykinin (BK), nitric oxide (NO), and guanosine cyclic 3Ј, 5Ј-monophosphate (cGMP). [3][4][5] This discovery turned attention to the possibility that the AT 2 receptor may mediate vasodilation, opposing the vasoconstrictor actions of Ang II at the AT 1 receptor. 6 Parallel cell signaling studies indicated that the AT 2 receptor is G-proteincoupled (through Gi␣) 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). AT 2 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 AT 1 receptor. 1,2,6,7 Work during the late 1990s through 2002 suggested that the AT 2 receptor might serve as a vasodilator counterforce to the AT 1 receptor. 2,6,7 However, vasorelaxation was difficult to elicit in some experimental models, attributed to the relatively low level of AT 2 receptor vascular expression compared with that of the AT 1 receptor. 1,6 To unmask the vasodilator action of the AT 2 receptor, experiments began to focus on eliminating the vasoconstrictor action of the AT 1 receptor with an AT 1 receptor blocker before and during AT 2 receptor stimulation. These studies demonstrated that AT 2 receptor activation by Ang II clearly dilated blood vessels and reduced blood pressure. 8,9 Studies also demonstrated that at least part of the depressor action of AT 1 receptor blockade is mediated by AT 2 receptor stimulation, in acute and chronic experimental models. 10,11 The vasodilator action of the AT 2 receptor was easier to detect during conditions in which the renin-angiotensin system was upregulated, such as sodium restriction, Ang II infusion, or renal vascular hypertension. 6,10,11 Most studies pointed to the role of BK, NO, and cGMP in mediating the observed vasodilator response via the AT 2 receptor. 6,7 So, is there anything new about the AT 2 receptor during the past 2 years? Yes, in many ways these have been "banner years" in promoting our underst...

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The multi‐faceted cross‐talk between the insulin and angiotensin II signaling systems

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