Mesangial AT(1)/B-2 receptor heterodimers contribute to angiotensin II hyperresponsiveness in experimental hypertension

Angiotensin 11 plays a central role in the pathogenesis of hypertension and of related cardiovascular disorders by binding to and activating angiotensin 11 receptors (AT, receptors). Sensitization to the vasopressor response of angiotensin H is a key feature in many cardiovascular disorders. However, underlying mechanisms responsible for angiotensin II hypersensitivity are barely understood. Because angiotensin 11 responsiveness of AT(1) receptors can be specifically modified by AT(1)/B-2 receptor dimerization, we determined the AT(1) receptor dimerization status in an experimental model of hypertension. AT(1)/B-2 receptor heterodimers were abundant on renal mesangial cells isolated from spontaneously hypertensive rats compared with that on cells from normotensive controls. Heterodimerization of AT(1) with B-2 receptors was correlated with high levels of B, receptor protein on kidneys and on mesangial cells of hypertensive rats, as determined in immunoblot with receptor-specific antibodies. Specific inhibition of AT(1)/B-2 receptor heterodimers revealed that these receptor heterodimers mediated an enhanced angiotensin II-stimulated G alpha(q/11) activation and an increased endothelin-1 secretion of mesangial cells from hypertensive rats. Thus, AT(1)/B-2 receptor heterodimerization contributes to angiotensin 11 hyperresponsiveness of mesangial cells in experimental hypertension.