PEDF Alleviates Diabetic Renal Fibrosis by Degrading Kidney Ectopic Fat Deposition and Inhibiting Metabolic Reprogramming of Renal Tubular Epithelial Cells.

Background: The pathogenesis of diabetic nephropathy (DKD) remains unclear; however, existing literature suggests that ectopic fat deposition and metabolic reprogramming contribute to the development of diabetic renal fibrosis. Our previous studies have demonstrated that pigment epithelium-derived factor (PEDF) can alleviate diabetic renal fibrosis. Methods: In this study, db/db mice were utilized as animal models to simulate type 2 diabetic nephropathy, and human proximal tubular epithelial cells (HK-2) cultured under conditions of high glucose and high palmitic acid were employed for in vitro analysis to investigate the mechanism through which PEDF improves diabetic renal fibrosis. Results: The results revealed that implanting the PEDF gene via AAV9 effectively improved renal function and blood lipid levels in db/db mice, and alleviated renal tubular injury, urinary albumin excretion, renal ectopic fat accumulation, and renal fibrosis in these mice. The protein expressions in renal peroxisomes and mitochondria could be up-regulated by PEDF, leading to enhanced β-oxidation of fatty acids in db/db mice. This effect was associated with the up-regulation of the ATGL-PPARα pathway and the down-regulation of the HIF-1α-HK2 pathway. It was observed that PEDF effectively mitigated lipid deposition and transdifferentiation of HK-2 cells by activating the ATGL-PPARα pathway, while concurrently inhibiting HIF-1α-HK2 pathway and glycolysis. Furthermore, PEDF facilitated fatty acid β-oxidation in both mitochondria and peroxisomes of HK-2 cells through the ATGL-PPARα pathway. Conclusion: PEDF can reduce abnormal renal fat accumulation and regulate metabolic reprogramming of renal tubular epithelial cells, thereby alleviating diabetic renal fibrosis.