GPR87 promotes renal tubulointerstitial fibrosis by accelerating glycolysis and mitochondrial injury.

Renal tubulointerstitial fibrosis is the hallmark of chronic kidney disease (CKD) and the best predictor of renal survival. However, current treatments for CKD remain extremely limited. Therefore, novel therapeutic targets are urgently needed to either stop or reverse CKD progression. The present study was designed to explore the potential role of GPR87, a member of the G protein-coupled receptors (GPCRs) family, in the pathogenesis of tubulointerstitial fibrosis. It was found that GPR87 was significantly induced in the kidney, especially in tubular areas, from different mouse models of renal fibrosis, including unilateral ureteral obstruction (UUO) nephropathy, aristolochic acid nephropathy, and diabetic nephropathy, respectively. Tubule-specific GPR87 deletion dramatically ameliorated tubulointerstitial fibrosis in UUO mice. Mechanistically, GPR87 accelerated glycolysis and mitochondrial injury by YAP-hexokinase-2 signaling, thereby promoting renal fibrosis. Importantly, the upregulation of GPR87 was also found in the kidney from patients with various CKD, indicating that the induction of GPR87 may be a common feature of human kidney diseases. Collectively, our studies for the first time demonstrate that GPR87 plays a pivotal role in renal fibrosis at least in part by accelerating glycolysis and mitochondrial injury, suggesting that targeting GPR87 may represent a novel therapeutic strategy for patients with CKD.