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

作者全名："Zhang, Fuwei; Lei, Lifu; Huang, Juan; Wang, Weiwei; Su, Qian; Yan, Hongjia; Chen, Caiyu; Zheng, Shuo; Ren, Hongmei; Li, Zhuxin; Jose, Pedro A.; Hu, Yijie; Si, Liangyi; Zeng, Chunyu; Yang, Jian"

作者地址："[Zhang, Fuwei; Wang, Weiwei; Si, Liangyi] Chongqing Med Univ, Affiliated Hosp 3, Dept Cardiol, Chongqing, Peoples R China; [Zhang, Fuwei; Lei, Lifu; Huang, Juan; Wang, Weiwei; Su, Qian; Yan, Hongjia; Si, Liangyi; Yang, Jian] Chongqing Med Univ, Res Ctr Metab & Cardiovasc Dis, Affiliated Hosp 3, Chongqing, Peoples R China; [Lei, Lifu; Huang, Juan; Yan, Hongjia; Yang, Jian] Chongqing Med Univ, Affiliated Hosp 3, Dept Clin Nutr, Chongqing, Peoples R China; [Su, Qian] Chongqing Med Univ, Dept Endocrinol, Affiliated Hosp 3, Chongqing, Peoples R China; [Chen, Caiyu; Zheng, Shuo; Ren, Hongmei; Li, Zhuxin; Zeng, Chunyu] Third Mil Med Univ, Dept Cardiol, Daping Hosp, Chongqing, Peoples R China; [Chen, Caiyu; Zheng, Shuo; Ren, Hongmei; Li, Zhuxin; Zeng, Chunyu] Chongqing Inst Cardiol, Chongqing Key Lab Hypertens Res, Chongqing Cardiovasc Clin Res Ctr, Chongqing, Peoples R China; [Jose, Pedro A.] George Washington Univ, Div Renal Dis & Hypertens, Dept Med, Sch Med & Hlth Sci, Washington, DC USA; [Jose, Pedro A.] George Washington Univ, Dept Physiol & Pharmacol, Sch Med & Hlth Sci, Washington, DC USA; [Hu, Yijie] Third Mil Med Univ, Daping Hosp, Dept Cardiovasc Surg, Chongqing, Peoples R China; [Zeng, Chunyu] Third Mil Med Univ, State Key Lab Trauma Burns & Combined Injury, Daping Hosp, Chongqing, Peoples R China; [Zeng, Chunyu] Univ Chinese Acad Sci, Chongqing Gen Hosp, Dept Cardiol, Cardiovasc Res Ctr,Chongqing Coll, Chongqing, Peoples R China"

通信作者："Si, LY (通讯作者)，Chongqing Med Univ, Affiliated Hosp 3, Dept Cardiol, Chongqing, Peoples R China.; Si, LY; Yang, J (通讯作者)，Chongqing Med Univ, Res Ctr Metab & Cardiovasc Dis, Affiliated Hosp 3, Chongqing, Peoples R China.; Yang, J (通讯作者)，Chongqing Med Univ, Affiliated Hosp 3, Dept Clin Nutr, Chongqing, Peoples R China.; Hu, YJ (通讯作者)，Third Mil Med Univ, Daping Hosp, Dept Cardiovasc Surg, Chongqing, Peoples R China."

来源：CLINICAL SCIENCE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000935719200001

JCR分区：Q1

影响因子：6

年份：2022

卷号：136

期号：12

开始页：989

结束页：1003

文献类型：Article

关键词：　

摘要："Activation of the angiotensin II type 2 receptor (AT(2)R) induces diuresis and natriuresis. Increased expression or/and activity of G-protein-coupled receptor kinase 4 (GRK4) or genetic variants (e.g., GRK41 gamma 42V) cause sodium retention and hypertension. Whether GRK4 plays a role in the regulation of AT(2)R in the kidney remains unknown. In the present study, we found that spontaneously hypertensive rats (SHRs) had increased AT(2)R phosphorylation and impaired AT(2)R-mediated diuretic and natriuretic effects, as compared with normotensive Wistar-Kyoto (WKY) rats. The regulation by GRK4 of renal AT(2)R phosphorylation and function was studied in human (h) GRK4 gamma transgenic mice. hGRK4 gamma 142V transgenic mice had increased renal AT(2)R phosphorylation and impaired AT(2)R-mediated natriuresis, relative to hGRK4 gamma wild-type (WT) littermates. These were confirmed in vitro; AT(2)R phosphorylation was increased and AT(2)R-mediated inhibition of Na+-K+-ATPase activity was decreased in hGRK4 gamma 142V, relative to hGRK4. WT-transfected renal proximal tubule (RPT) cells. There was a direct physical interaction between renal GRK4 and AT(2)R that was increased in SHRs, relative to WKY rats. Ultrasound-targeted microbubble destruction of renal GRK4 decreased the renal AT(2)R phosphorylation and restored the impaired AT(2)R-mediated diuresis and natriuresis in SHRs. In vitro studies showed that GRK4 siRNA reduced AT(2)R phosphorylation and reversed the impaired AT(2)R-mediated inhibition of Na+-K+-ATPase activity in SHR RPT cells. Our present study shows that GRK4, at least in part, impairs renal AT(2)R-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 AT(2)R."

基金机构："National Natural Science Foundation of China [31730043, 82070442]; National Key R&D Program of China [2018YFC1312700]; Program of Innovative Research Team by National Natural Science Foundation [81721001]; Program of Chongqing Medical University for Youth Innovation in Future Medicine [W0085]; Joint Program of Chongqing Health Commission and Science and Technology Bureau [2018ZDXM003]; National Institutes of Health [P01HL074940, DK039308, DK119652]"

基金资助正文："This work was supported in part by grants from the National Natural Science Foundation of China [grant numbers 31730043 and 82070442]; National Key R&D Program of China [grant number 2018YFC1312700]; Program of Innovative Research Team by National Natural Science Foundation [grant number 81721001]; Program of Chongqing Medical University for Youth Innovation in Future Medicine [grant number W0085]; Joint Program of Chongqing Health Commission and Science and Technology Bureau [grant number 2018ZDXM003]; and the National Institutes of Health [grant numbers P01HL074940, DK039308, and DK119652]."