Human GRK4γ142V Variant Promotes Angiotensin II Type I Receptor-Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition

The influence of a single gene on the pathogenesis of essential hypertension may be difficult to ascertain, unless the gene interacts with other genes that are germane to blood pressure regulation. G-protein-coupled receptor kinase type 4 (GRK4) is one such gene. We have reported that the expression of its variant hGRK4(142V) in mice results in hypertension because of impaired dopamine D-1 receptor. Signaling through dopamine D-1 receptor and angiotensin II type I receptor (AT(1)R) reciprocally modulates renal sodium excretion and blood pressure. Here, we demonstrate the ability of the hGRK4(142V) to increase the expression and activity of the AT(1)R. We show that hGRK4(142V) phosphorylates histone deacetylase type 1 and promotes its nuclear export to the cytoplasm, resulting in increased AT(1)R expression and greater pressor response to angiotensin II. AT(1)R blockade and the deletion of the Agtr1a gene normalize the hypertension in hGRK4(142V) mice. These findings illustrate the unique role of GRK4 by targeting receptors with opposite physiological activity for the same goal of maintaining blood pressure homeostasis, and thus making the GRK4 a relevant therapeutic target to control blood pressure.