Role of GRK4 in the Regulation of Arterial AT1 Receptor in Hypertension

G-protein–coupled receptor kinase 4 (GRK4) gene variants, via impairment of renal dopamine receptor and enhancement of renin–angiotensin system functions, cause sodium retention and increase blood pressure. Whether GRK4 and the angiotensin type 1 receptor (AT1R) interact in the aorta is not known. We report that GRK4 is expressed in vascular smooth muscle cells of the aorta. Heterologous expression of the GRK4γ variant 142V in A10 cells increased AT1R protein expression and AT1R-mediated increase in intracellular calcium concentration. The increase in AT1R expression was related to an increase in AT1R mRNA expression via the NF-κB pathway. As compared with control, cells expressing GRK4γ 142V had greater NF-κB activity with more NF-κB bound to the AT1R promoter. The increased AT1R expression in cells expressing GRK4γ 142V was also associated with decreased AT1R degradation, which may be ascribed to lower AT1R phosphorylation. There was a direct interaction between GRK4γ and AT1R that was decreased by GRK4γ 142V. The regulation of AT1R expression by GRK4γ 142V in A10 cells was confirmed in GRK4γ 142V transgenic mice; AT1R expression was higher in the aorta of GRK4γ 142V transgenic mice than control GRK4γ wild-type mice. Angiotensin II–mediated vasoconstriction of the aorta was also higher in GRK4γ 142V than in wild-type transgenic mice. This study provides a mechanism by which GRK4, via regulation of arterial AT1R expression and function, participates in the pathogenesis of conduit vessel abnormalities in hypertension.