GPR56 Promotes Diabetic Kidney Disease Through eNOS Regulation in Glomerular Endothelial Cells

作者全名："Wu, Jinshan; Wang, Zhihong; Cai, Minchao; Wang, Xuan; Lo, Benjamin; Li, Qifu; He, John Cijiang; Lee, Kyung; Fu, Jia"

作者地址："[Wu, Jinshan; Wang, Zhihong; Cai, Minchao; Wang, Xuan; Lo, Benjamin; He, John Cijiang; Lee, Kyung; Fu, Jia] Icahn Sch Med Mt Sinai, Dept Med, Div Nephrol, New York, NY 10029 USA; [Wu, Jinshan] Chongqing Med Univ, Dept Endocrinol, Affiliated Hosp 1, Chongqing, Peoples R China; [Wang, Zhihong; Li, Qifu] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrinol, Chongqing, Peoples R China; [He, John Cijiang] James J Peters Vet Affairs Med Ctr, Renal Program, Bronx, NY 10468 USA"

通信作者："He, JC; Lee, K; Fu, J (通讯作者)，Icahn Sch Med Mt Sinai, Dept Med, Div Nephrol, New York, NY 10029 USA.; He, JC (通讯作者)，James J Peters Vet Affairs Med Ctr, Renal Program, Bronx, NY 10468 USA."

来源：DIABETES

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001126701500013

JCR分区：Q1

影响因子：6.2

年份：2023

卷号：72

期号：11

开始页：1652

结束页：1663

文献类型：Article

关键词：　

摘要："Although glomerular endothelial dysfunction is well recognized as contributing to the pathogenesis of diabetic kidney disease (DKD), the molecular pathways contributing to DKD pathogenesis in glomerular endothelial cells (GECs) are only partially understood. To uncover pathways that are differentially regulated in early DKD that may contribute to disease pathogenesis, we recently conducted a transcriptomic analysis of isolated GECs from diabetic NOS3-null mice. The analysis identified several potential mediators of early DKD pathogenesis, one of which encoded an adhesion G protein-coupled receptor-56 (GPR56), also known as ADGRG1. Enhanced glomerular expression of GPR56 was observed in human diabetic kidneys, which was negatively associated with kidney function. Using cultured mouse GECs, we observed that GPR56 expression was induced with exposure to advanced glycation end products, as well as in high-glucose conditions, and its overexpression resulted in decreased phosphorylation and expression of endothelial nitric oxide synthase (eNOS). This effect on eNOS by GPR56 was mediated by coupling of G alpha(12/13)-RhoA pathway activation and G alpha i-mediated cAMP/PKA pathway inhibition. The loss of GPR56 in mice led to a significant reduction in diabetes-induced albuminuria and glomerular injury, which was associated with reduced oxidative stress and restoration of eNOS expression in GECs. These findings suggest that GPR56 promotes DKD progression mediated, in part, through enhancing glomerular endothelial injury and dysfunction."

基金机构："National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [K01DK125614-01A1]; NIH NIDDK [R01DK117913-01, R01DK129467, R01DK133912, R01DK109683, R01DK122980, P01DK56492]; VA Merit Award [I01BX000345]"

基金资助正文："J.F. is supported by the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant K01DK125614-01A1; J.C.H. is supported by NIH NIDDK grants R01DK109683, R01DK122980, R01DK129467, and P01DK56492, and VA Merit Award I01BX000345; K.L. is supported by NIH NIDDK grants R01DK117913-01, R01DK129467, and R01DK133912."