GPR56 promotes diabetic kidney disease through eNOS regulation in glomerular endothelial cells

Although glomerular endothelial dysfunction is well-recognized to contribute 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. Utilizing cultured mouse GECs, we observed that GPR56 expression was induced with exposure to advanced glycation endproducts, 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 Gα_12/13-RhoA pathway activation and Gαi-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.

Article Highlights

· Glomerular endothelial cell dysfunction is a key component of diabetic kidney disease pathogenesis, but underlying molecular mechanisms are not entirely understood.

· Unbiased expression identified GPR56, a versatile adhesion G protein-coupled receptor, as a potential mediator of glomerular endothelial cell function in DKD, but its role in endothelial or kidney cells was not well understood.

· The current study unravels the role of GPR56 in glomerular endothelial cells in DKD and demonstrates it as a key mediator of DKD progression.

· The targeting of GRP56 may be a novel therapeutic approach in DKD.