Inhibition of Drp1-mediated mitochondrial fission by P110 ameliorates renal injury in diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease, characterized by progressive renal injury driven by mitochondrial dysfunction and metabolic reprogramming. Excessive mitochondrial fission, mediated by dynamin-related protein 1 (Drp1), contributes to mitochondrial fragmentation and cellular injury in the diabetic kidney. Here, we investigate the therapeutic potential of P110, a selective inhibitor of Drp1-mediated mitochondrial fission, in experimental models of DN. We demonstrate that P110 effectively reduces mitochondrial fragmentation and restores metabolic balance in renal tubular cells from DN patients. In streptozotocin (STZ)-induced diabetic mice and db/db mice, P110 treatment significantly mitigates renal injury, as evidenced by decreased fibrosis, inflammation, and podocyte injury, despite having no impact on hyperglycemia or body weight loss. Mechanistically, P110 disrupts the interaction between Drp1 and Fis1, thereby inhibiting mitochondrial fission, and activates the AMPK/PGC-1α/TFAM pathway, promoting mitochondrial biogenesis and function. Our findings suggest that targeting mitochondrial fission with P110 offers a novel therapeutic strategy for preventing and treating DN, potentially addressing a critical gap in current diabetic nephropathy management.

Keywords: Diabetic nephropathy; Drp1; Fis1; Metabolic reprogramming; Mitochondria.