An aldose reductase inhibitor, WJ-39, ameliorates renal tubular injury in diabetic nephropathy by activating PINK1/Parkin signaling

Renal tubular injury is a critical factor during the early stages of diabetic nephropathy (DN). Proximal tubular epithelial cells, which contain abundant mitochondria essential for intracellular homeostasis, are susceptible to disruptions in the intracellular environment, making them especially vulnerable to diabetic state disorders, which may be attributed to their elevated energy requirements and reliance on aerobic metabolism. It is widely thought that overactivation of the polyol pathway is implicated in DN pathogenesis, and inhibition of Aldose Reductase (AR), the rate-limiting Enzyme in this pathway, represents a promising therapeutic avenue. WJ-39, a novel Aldose Reductase Inhibitor, was investigated in this study for its protective effects on renal tubules in DN and the underlying mechanisms. Our findings revealed that WJ-39 significantly ameliorated the renal tubular morphology in high-fat diet (HFD)/streptozotocin (STZ)-induced DN rats, concurrently inhibiting fibrosis. Notably, WJ-39 safeguarded the structure and function of renal tubular mitochondria by enhancing mitochondrial dynamics. This involved the regulation of mitochondrial fission and fusion proteins and the promotion of PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated Mitophagy. Furthermore, WJ-39 demonstrated the inhibition of endogenous Apoptosis by mitigating the production of mitochondrial Reactive Oxygen Species (ROS). The protective effects of WJ-39 on mitochondria and Apoptosis were countered in high glucose-treated HK-2 cells upon transfection with PINK1 siRNA. Overall, our findings suggest that WJ-39 protects the structural and functional integrity of renal tubules in DN, which may be attributed to its capacity to inhibit Aldose Reductase activity, activate the PINK1/Parkin signaling pathway, promote Mitophagy, and alleviate Apoptosis.

Aldose reductase; Apoptosis; Diabetic nephropathy; Mitophagy; Renal tubule.