G-protein coupled receptor GPR124 protects against podocyte senescence and injury in diabetic kidney disease

Although emerging studies highlight the pivotal role of podocyte senescence in the pathogenesis of diabetic kidney disease (DKD) and aging-related kidney diseases, therapeutic strategies for preventing podocyte senescence are still lacking. Here, we identified a previously unrecognized role of GPR124, a novel adhesion G protein-coupled receptor, in maintaining podocyte structure and function by regulation of cellular senescence in DKD. Podocyte GPR124 was significantly reduced in db/db diabetic (a type 2 diabetic mouse model) and streptozocin-induced diabetic mice (a type 1 diabetic model), which was further confirmed in kidney biopsies from patients with DKD. The level of GPR124 in glomeruli was positively correlated with the estimated glomerular filtration rate and negatively correlated with serum creatinine levels. Podocyte-specific deficiency of GPR124 significantly aggravated podocyte injury and proteinuria in the two models of diabetic mice. Moreover, GPR124 regulated podocyte senescence in both diabetic and aged mice. Mechanistically, GPR124 directly bound with vinculin and negatively regulated focal adhesion kinase (FAK) signaling, thereby mediating podocyte senescence and function. Importantly, overexpression of GPR124 or pharmacological inhibition of FAK protected against podocyte senescence and injury under diabetic conditions. Our studies suggest that targeting GPR124 may be an innovative therapeutic strategy for patients with DKD and aging-related kidney diseases.