G-protein-coupled receptor kinase 4 causes renal angiotensin II type 2 receptor dysfunction by increasing its phosphorylation

Fuwei Zhang, Department of Cardiology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Lifu Lei, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Juan Huang, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Weiwei Wang, Department of Cardiology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Qian Su, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Hongjia Yan, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Caiyu Chen, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.
Shuo Zheng, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.
Hongmei Ren, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.
Zhuxin Li, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.
Pedro A. Jose, Division of Renal Diseases and Hypertension, Department of Medicine and Department of Physiology and Pharmacology, The George Washington University School of Medicine and Health Sciences, Washington, DC, U.S.A.
Yijie Hu, Department of Cardiovascular Surgery, Daping Hospital, The Third Military Medical University, Chongqing, China.
Liangyi Si, Department of Cardiology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Chunyu Zeng, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.
Jian Yang, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Document Type

Journal Article

Publication Date

6-30-2022

Journal

Clinical science (London, England : 1979)

Volume

136

Issue

12

DOI

10.1042/CS20220236

Keywords

G protein-coupled receptor kinase 4; angiotensin type 2 receptor; kidney; phosphorylation

Abstract

Activation of the angiotensin II type 2 receptor (AT2R) induces diuresis and natriuresis. Increased expression or/and activity of G-protein-coupled receptor kinase 4 (GRK4) or genetic variants (e.g., GRK4γ142V) cause sodium retention and hypertension. Whether GRK4 plays a role in the regulation of AT2R in the kidney remains unknown. In the present study, we found that spontaneously hypertensive rats (SHRs) had increased AT2R phosphorylation and impaired AT2R-mediated diuretic and natriuretic effects, as compared with normotensive Wistar-Kyoto (WKY) rats. The regulation by GRK4 of renal AT2R phosphorylation and function was studied in human (h) GRK4γ transgenic mice. hGRK4γ142V transgenic mice had increased renal AT2R phosphorylation and impaired AT2R-mediated natriuresis, relative to hGRK4γ wild-type (WT) littermates. These were confirmed in vitro; AT2R phosphorylation was increased and AT2R-mediated inhibition of Na+-K+-ATPase activity was decreased in hGRK4γ142V, relative to hGRK4γ WT-transfected renal proximal tubule (RPT) cells. There was a direct physical interaction between renal GRK4 and AT2R that was increased in SHRs, relative to WKY rats. Ultrasound-targeted microbubble destruction of renal GRK4 decreased the renal AT2R phosphorylation and restored the impaired AT2R-mediated diuresis and natriuresis in SHRs. In vitro studies showed that GRK4 siRNA reduced AT2R phosphorylation and reversed the impaired AT2R-mediated inhibition of Na+-K+-ATPase activity in SHR RPT cells. Our present study shows that GRK4, at least in part, impairs renal AT2R-mediated diuresis and natriuresis by increasing its phosphorylation; inhibition of GRK4 expression and/or activity may be a potential strategy to improve the renal function of AT2R.

Department

Medicine

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