Human GRK4ÃŽÂ³142V variant promotes AT1R-mediated hypertension via renal HDAC1 inhibition and predicts the blood pressure response to angiotensin receptor blockade

Pedro A Jose

doi:10.4172/2161-0959.C1.025

Human GRK4ÃÅ½ÃÂ³142V variant promotes AT1R-mediated hypertension via renal HDAC1 inhibition and predicts the blood pressure response to angiotensin receptor blockade

6^th Annual conference on Clinical & Pediatric Nephrology

May 09-10, 2016 New Orleans, USA

Pedro A Jose

The George Washington University School of Medicine & Health Sciences, USA

Posters & Accepted Abstracts: J Nephrol Ther

Abstract :

The influence of a single gene on the etiology of essential hypertension may be difficult to ascertain, unless the gene interacts with other genes that are germane to blood pressure (BP) regulation. G protein-coupled receptor kinase type 4 (GRK4) is one such gene. Nonsynonymous GRK4 variants, R65L, A142V and A486V are associated with essential hypertension. The dopamine D1 receptor (D1R) and angiotensin II type-I receptor (AT1R) reciprocally regulate renal sodium excretion and BP. hGRK4�?³142V transgenic mice have high blood pressure (BP) due to the impairment of the natriuretic function of D1R and increased expression and activity of the AT1R, that counteract the renal physiological effects of the D1R. hGRK4�?³142V phosphorylates histone deacetylase type-1 (HDAC1) but not HDAC2 and promotes HDAC1 export from the nucleus to the cytoplasm, resulting in increased AT1R expression. There is specificity of these effects because GRK4WT, but not GRK2WT, decreases AT1R expression. Moreover, AT1R blockade and the deletion of the Agtr1a gene normalize the hypertension in hGRK4�?³142V mice. The studies in mice can be translated to humans. In 829 patients with essential hypertension we found that carriers of hGRK4�?³142V had a greater decrease in systolic BP in response to angiotensin receptor blockers (ARBs) than non-carrier hypertensive patients. By contrast, those with variants only at hGRK4�?³486V were less likely to achieve the BP goal in response to an ARB than those with no variants. These findings illustrate the unique role of GRK4 by targeting receptors with opposite physiological activity for the same goal of maintaining BP homeostasis and thus making the GRK4 a relevant therapeutic target to control BP.