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A8234 Role of GRK4 in the regulation of renal ETB receptor in hypertension

Objectives: To study the role of G protein-coupled receptor kinase 4 (GRK4) in the regulation of endothelin receptor B (ETBR) in hypertension. Methods: Male anaesthetic spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were used to test ETBR-mediated natriuresis and diuresis. The ETBR agonist, BQ-3020 (0.1, 0.5, 1.0Ymg/kg/min) were infused via supra-renal artery at a rate of 0.04Yml/min for 40Ymin. The same experiments were conducted in GRK4 A142 V transgenic mice to confirm the relationship between GRK4 and ETBR hyper-phosphorylation. Co-immunoprecipitation and confocal microscopy were conducted to test interaction between GRK4 and ETBR. Results: Activation of ETBR induced natriuresis and diuresis in WKY rats, which was impaired in SHRs. ETBR phosphorylation was higher in SHRs as compared with WKY rats, although ETBR expression had no difference in kidneys from WKY and SHRs. Activation of ETBR induced natriuresis in wild-type mice, however, in GRK4 transgenic mice, the ETBR-mediated natriuresis and diuresis was lost, accompanied with higher ETBR hyper-phosphorylation. There were co-localization and co-immunoprecipitation between ETBR and GRK4 in RPT cells both from WKY and SHRs, the ETBR/GRK4 linkage was higher in SHR cells than in WKY cells. Down-regulation of GRK4 with siRNA recovered ETBR function, which is pathophysiological significance, because down-regulation of renal GRK4 expression via ultrasound-targeted microbubble destruction restored ETBR-mediated natriuresis and diuresis in SHRs, accompanied with lowered ETBR phosphorylation. Conclusion: This study provides a mechanism by which GRK4, via regulation of renal ETBR function, participates in the pathogenesis of hypertension.