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

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

  • Clin Sci (Lond). 2022 Jun 30;136(12):989-1003. doi: 10.1042/CS20220236.
Fuwei Zhang  # 1 2,  Lifu Lei  # 2 3,  Juan Huang 2 3,  Weiwei Wang 1 2,  Qian Su 2 4,  Hongjia Yan 2 3,  Caiyu Chen 5 6,  Shuo Zheng 5 6,  Hongmei Ren 5 6,  Zhuxin Li 5 6,  Pedro A Jose 7,  Yijie Hu 8,  Liangyi Si 1 2,  Chunyu Zeng 5 6 9 10,  Jian Yang 2 3
Affiliations

Affiliations

  • 1 Department of Cardiology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2 Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 3 Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 4 Department of Endocrinology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 5 Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.
  • 6 Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, P. R. China.
  • 7 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.
  • 8 Department of Cardiovascular Surgery, Daping Hospital, The Third Military Medical University, Chongqing, China.
  • 9 State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University, Chongqing, China.
  • 10 Cardiovascular Research Center of Chongqing College, Department of Cardiology of Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China.
  • # Contributed equally.
PMID: 35695067 DOI: 10.1042/CS20220236
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.

Keywords

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

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