Abstract-Abnormalities in D 1 dopamine receptor function in the kidney are present in some types of human essential and rodent genetic hypertension. We hypothesize that increased activity of G protein-coupled receptor kinase type 4 (GRK4) causes the impaired renal D 1 receptor function in hypertension. We measured renal GRK4 and D 1 and serine-phosphorylated D 1 receptors and determined the effect of decreasing renal GRK4 protein by the chronic renal cortical interstitial infusion (4 weeks) of GRK4 antisense oligodeoxynucleotides (As-Odns) in conscious-uninephrectomized spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar-Kyoto (WKY) rats. Basal GRK4 expression and serine-phosphorylated D 1 receptors were Ϸ90% higher in SHRs than in WKY rats and were decreased to a greater extent in SHRs than in WKY rats with GRK4 As-Odns treatment. Basal renal D 1 receptor protein was similar in both rat strains. GRK4 As-Odns, but not scrambled oligodeoxynucleotides, increased sodium excretion and urine volume, attenuated the increase in arterial blood pressure with age, and decreased protein excretion in SHRs, effects that were not observed in WKY rats. These studies provide direct evidence of a crucial role of renal GRK4 in the D 1 receptor control of sodium excretion and blood pressure in genetic hypertension. The uncoupling of the D 1 -like receptor from its effector proteins in the kidney in hypertension is associated with increased phosphorylation of the D 1 receptor. 4,5 In human essential hypertension, single nucleotide polymorphisms of the G protein-coupled receptor (GPCR) kinase 4 (GRK4) are associated with constitutive phosphorylation and desensitization of the D 1 receptor in renal proximal tubules. 4 -6 These lead to sodium retention and hypertension. Indeed, transgenic mice expressing the GRK4 variant, GRK4␥A142V, develop hypertension that is associated with an impaired D 1 receptormediated natriuresis. 5 To determine whether aberrant GRK4 function contributes to the impaired renal D 1 receptor function in SHRs, we studied the renal expression of GRK4 and the effects of decreasing its expression in the kidney by a chronic renal cortical interstitial infusion of GRK4 antisense (As) oligodeoxynucleotides (Odns) in conscious SHRs and their normotensive controls, Wistar-Kyoto (WKY) rats. If an increased GRK4 activity in the kidney is responsible for the increased blood pressure in SHRs, this maneuver should improve D 1 receptor-mediated renal tubular handling of sodium and ameliorate the high blood pressure in SHRs without affecting these variables in WKY rats.