Mesangial AT<SUB>1</SUB>/B<SUB>2</SUB> Receptor Heterodimers Contribute to Angiotensin II Hyperresponsiveness in Experimental Hypertension

Abstract

Angiotensin II plays a central role in the pathogenesis of hypertension and of related cardiovascular disorders by binding to and activating angiotensin II receptors (AT1 receptors). Sensitization to the vasopressor response of angiotensin II is a key feature in many cardiovascular disorders. However, underlying mechanisms responsible for angiotensin II hypersensitivity are barely understood. Because angiotensin II responsiveness of AT1 receptors can be specifically modified by AT1/B2 receptor dimerization, we determined the AT1 receptor dimerization status in an experimental model of hypertension. AT1/B2 receptor heterodimers were abundant on renal mesangial cells isolated from spontaneously hypertensive rats compared with that on cells from normotensive controls. Heterodimerization of AT1 with B2 receptors was correlated with high levels of B2 receptor protein on kidneys and on mesangial cells of hypertensive rats, as determined in immunoblot with receptor-specific antibodies. Specific inhibition of AT1/B2 receptor heterodimers revealed that these receptor heterodimers mediated an enhanced angiotensin II-stimulated Galphaq/11 activation and an increased endothelin-1 secretion of mesangial cells from hypertensive rats. Thus, AT1/B2 receptor heterodimerization contributes to angiotensin II hyperresponsiveness of mesangial cells in experimental hypertension.

Functional interactions between 7TM receptors in the Renin-Angiotensin System—Dimerization or crosstalk?

“…From these studies, they derive three important pharmacological conclusions: First; the AT1R and the B2R form heterodimers in all the cellular systems examined both including different cell lines (24), and primary cells such as vascular smooth muscle cells (24), neurons (12) and platelets (14). These data indicate that the system is "universal" and that AT1R/B2R heterodimerization occurs as a natural consequence of simultaneous expression of AT1R and B2R within the same cell (12,14,24). Second; when compared to the individually expressed receptors, the AT1R/B2R…”

“…Quitterer and co-workers have reported, that the AT1R forms heterodimers with the B2R (12,14,24). From these studies, they derive three important pharmacological conclusions: First; the AT1R and the B2R form heterodimers in all the cellular systems examined both including different cell lines (24), and primary cells such as vascular smooth muscle cells (24), neurons (12) and platelets (14).…”

“…AT1R and B2R are naturally co-expressed in several cell types (78,79) From a medical perspective, the AT1R/B2R interaction would be of outstanding value, stressed by the finding by Abdalla et al, that B2 upregulation and AT1R potentiation can be linked to experimental hypertension (12), vascular smooth muscle cell contraction (24), and preeclampsia (14). The proposed disease relevance of the dimer implies that development of AT1R/B2R…”

“…Even though it has been demonstrated that GPCRs can signal as monomeric units (7,8), there is mounting evidence that 7TM receptors may form both homo-and heterodimers, and that dimerization could be important for receptor function, with respect to ligand binding, receptor activation, desensitization, and trafficking (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). In this regard, the AT1R is particularly well studied (se figure 1).…”

“…In this regard, the AT1R is particularly well studied (se figure 1). For example, it has been shown that the AT1R decreases Gαq coupling when the receptor interacts with either the MAS receptor or the AT2R (13,(17)(18)(19), while, its interaction with the Bradykinin B2 Receptor (B2R) enhances signalling (12,14,24). The AT1R can also form complexes with the beta 2 adrenergic receptors (β2AR) and it is possible to achieve dual receptor inhibition of AT1R and β2AR signalling using only a single receptor antagonist (16).…”