Role of GRK4 in the regulation of the renal ETB receptor in hypertension. Issue 9 (20th July 2020)

• Record Type: Journal Article
• Authors: Yang, Yang; Li, Meixiang; Zou, Xue; Chen, Caiyu; Zheng, Shuo; Fu, Chunjiang; Chen, Ken; Jose, Pedro A.; Lan, Cong; Liu, Yukai
• Is Part Of: FASEB journal. Volume 34:Issue 9(2020)
• Page Start: 11594
• Page End: 11604
• Publication Date: 2020-07-20
• Subjects: endothelin type B receptor -- G protein‐coupled receptor kinase 4 -- hypertension -- natriuresis; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.201902552R
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: The endothelin receptor type B (ETBR) regulates water and electrolyte balance and blood pressure, in part, by inhibiting renal sodium transport. Our preliminary study found that the ETBR‐mediated diuresis and natriuresis are impaired in hypertension with unknown mechanism. Persistently increased activity of G protein‐coupled receptor kinase 4 (GRK4), caused by increased expression or genetic variants (eg, GRKγ142V), impairs the ability of the kidney to excrete a sodium load, in part, by impairing renal dopamine D1 receptor function through persistent phosphorylation. Our present study found that although renal ETBR expression was not different between Wistar‐Kyoto (WKY) and spontaneously hypertensive rats (SHRs), renal ETBR phosphorylation was higher in SHRs. The role of hyper‐phosphorylation in impaired ETBR‐function was supported by results in human (h) GRK4γ transgenic mice. Stimulation of ETBR by BQ3020‐induced natriuresis in human (h) GRK4γ wild‐type (WT) mice. However, in hGRK4γ 142V transgenic mice, the renal ETBR was hyperphosphorylated and ETBR‐mediated natriuresis and diuresis were not evident. There were co‐localization and co‐immunoprecipitation of ETBR and GRK4 in renal proximal tubule (RPT) cells from both WKY and SHRs but was greater in the latter than the former group. SiRNA‐mediated downregulation of GRK4 expression, recovered the impaired inhibitory effect of ETBR on Na + ‐K + ‐ATPase activity in RPT cells from SHR. In vivo downregulation of renal GRK4 expression, via ultrasound‐targeted microbubble destruction, decreased ETBR phosphorylation and restored ETBR‐mediated natriuresis and diuresis in SHRs. This study provides a mechanism by which GRK4, via regulation of renal ETBR function, participates in the pathogenesis of hypertension.