Effects of Decreased Renal Cortical Expression of G Protein-Coupled Receptor Kinase 4 and Angiotensin Type 1 Receptors in Rats

Abnormalities in renal angiotensin type 1 receptor (AT1R), D1 dopamine receptor (D1R) and G protein-coupled receptor kinase 4 (GRK4) are present in polygenic hypertension. Selective renal reduction of AT1R expression by intrarenal cortical infusion of antisense oligodeoxynucleotides (As-Odns) in conscious, uninephrectomized, sodium-loaded rats decreases proteinuria, normalizes the glomerular sclerosis index (GSI), increases the sodium excretion (UNaV), and modestly increases blood pressure (BP) in spontaneously hypertensive rats (SHR) but not in normotensive Wistar-Kyoto rats (WKY). In contrast, selective renal reduction of GRK4 expression by infusion of GRK4 As-Odns increases UnaV, attenuates the increase in arterial BP with age, and modestly decreases protein excretion in SHR, but not in WKY. In this study, we report that intrarenal cortical infusion of both GRK4 and AT1R As-Odns decreased BP and increased UNaV in SHR; these effects were also noted in WKY to a lesser extent. Infusion of SHR with this combination of As-Odns resulted in a decrease in proteinuria and improvement of GSI similar to those by AT1R As-Odn only. In contrast to the increased circulating angiotensin II and aldosterone levels induced by AT1R As-Odn alone, the combination of As-Odns decreased both, contributing to greater natriuresis and amelioration of hypertension than by GRK4 or AT1R As-Odn only. Our results indicate an interaction between GRK4-regulated receptors and the renin-angiotensin system in the regulation of renal function and BP.