G protein kinase 4gammaA142V overexpression induced hypertension by downregulating D1 receptors in transgenic mice / 中华心血管病杂志

ABSTRACT

<p><b>OBJECTIVE</b>Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. We investigated the role of G protein kinase (GRK) 4gamma in essential hypertension in GRK4gamma mutant A142V transgenic mice.</p><p><b>METHODS</b>Blood pressure, renal sodium excretion, D(1) receptor protein expression and phosphorylation were measured in GRK4gammaA142V transgenic mice and control mice. Moreover, the effects of GRK4 inhibition by antisense oligonucleotides on D(1) receptor expressions were determined in HK-2 cells.</p><p><b>RESULTS</b>As compared with their control mice, GRK4gammaA142V transgenic mice had higher blood pressure, lower D(1) receptor expression (0.6 +/- 0.2 vs. 1.5 +/- 0.2, P < 0.05), higher D(1) receptor phosphorylation [(65 +/- 7) DU vs. (35 +/- 7) DU, P < 0.05] in renal cortical membranes and the diuretic and natriuretic effects after stimulation of renal D(1) receptor were impaired in GRK4gammaA142V transgenic mice. Inhibition of GRK4 expression (0.60 +/- 0.10 vs. 1.30 +/- 0.09, P < 0.05) by GRK4 antisense oligonucleotides upregulated D(1) receptor expression (1.5 +/- 0.2 vs. 0.8 +/- 0.1, P < 0.05) in HK-2 cells.</p><p><b>CONCLUSIONS</b>Our results show that GRK4gammaA142V overexpression induced hypertension is mediated by dowregulated renal D(1) receptor expressions in GRK4gammaA142V transgenic mice.</p>