Cardiovascular and renal regulation by the angiotensin type 2 receptor: the AT2 receptor comes of age.

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 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). 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 AT1 receptor.1,6 To unmask the vasodilator action of the AT2 receptor, experiments began to focus on eliminating the vasoconstrictor action of the AT1 receptor with an AT1 receptor blocker before and during AT2 receptor stimulation. These studies demonstrated that AT2 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 AT1 receptor blockade is mediated by AT2 receptor stimulation, in acute and chronic experimental models.10,11 The vasodilator action of the AT2 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 AT2 receptor.6,7 So, is there anything new about the AT2 receptor during the past 2 years? Yes, in many ways these have been “banner years” in promoting our understanding of the AT2 receptor, validating previous observations, and elucidating new roles for the receptor in cardiovascular and renal function.1 Studies have unequivocally confirmed the role of the AT2 receptor as a vasodilator mediator in resistance microvessels as well as in large capacitance vessels.2 AT2 receptor stimulation of BK, NO, and cGMP formation is a consistent signaling pathway for vasodilation.3 An additional cell signaling pathway, phospholipase D, has been identified for the AT2 receptor.4 The AT2 receptor inhibits renin biosynthesis and release.5 The AT2 receptor appears to have a protective role in ischemic nephropathy.6 The AT2 receptor is cadioprotective after myocardial infarction and during states of Ang II excess; these beneficial responses also are mediated by BK and NO.7 An AT2 receptor gene polymorphism is associated with coronary disease in men.