AT2 Receptors: Potential Therapeutic Targets for Hypertension

Abstract

The renin–angiotensin system (RAS) is arguably the most important and best studied hormonal system in the control of blood pressure (BP) and the pathogenesis of hypertension. The RAS features its main effector angiotensin II (Ang II) acting via its 2 major receptors, angiotensin type-1(AT₁R) and type-2 (AT₂R). In general, AT₂Rs oppose the detrimental actions of Ang II via AT₁Rs. AT₂R activation induces vasodilation and natriuresis, but its effects to lower BP in hypertension have not been as clear as anticipated. Recent studies, however, have demonstrated that acute and chronic AT₂R stimulation can induce natriuresis and lower BP in the Ang II infusion model of experimental hypertension. AT₂R activation induces receptor recruitment from intracellular sites to the apical plasma membranes of renal proximal tubule cells via a bradykinin, nitric oxide, and cyclic guanosine 3′,5′ monophosphate signaling pathway that results in internalization and inactivation of sodium (Na⁺) transporters Na⁺–H⁺ exchanger-3 and Na⁺/K⁺ATPase. These responses do not require the presence of concurrent AT₁R blockade and are effective both in the prevention and reversal of hypertension. This review will address the role of AT₂Rs in the control of BP and Na⁺ excretion and the case for these receptors as potential therapeutic targets for hypertension in humans.