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.