Sitagliptin ameliorates renal tubular injury in diabetic kidney disease via STAT3-dependent mitochondrial homeostasis through SDF-1α/CXCR4 pathway.

Abstract

Mitochondrial abnormalities play critical roles in diabetic tubular injury progression. Dipeptidyl peptidase-4 (DPP4) inhibitors are widely used antihyperglycemicagents that exert renal protective and positive effects against mitochondrial dysfunction in diabetic kidney disease (DKD). However, their underlying mechanism remains unclear. In this study, DPP4 upregulation, mitochondrial fragmentation, and altered mitochondrial dynamics-associated protein expression were observed in the tubules ofDBA2/J (D2) diabetic mice with unilateral nephrectomy and in albumin-stimulated tubular cells. The inhibition of DPP4 by sitagliptin(Sita) ameliorated these mitochondrial perturbations bothin vivoandin vitro, whereas DPP4 overexpression aggravated mitochondrial fusion-fission disorder and tubular cell injury in albumin-treated HK-2 cells. Downstream of DPP4,the SDF-1α/CXCR4 pathway was significantly suppressed in diabetic tubules. After Sitatreatment, this signaling pathway was restored, and themitochondrial dynamics was improved. Furthermore, a direct interaction between STAT3 and OPA1 was found inthe mitochondria oftubular cells, and this effect was weakened by overloading albumin andby CXCR4 siRNA treatment, suggesting a possible link between DPP4-mediated SDF-1α/CXCR4/STAT3 signaling and mitochondrial dysfunction in diabetic tubular cells. The results suggest that a novel mechanism links the DPP4 enzyme to impaired mitochondrial dynamics homeostasis during tubular injury in DKD and highlight that the SDF-1α/CXCR4/STAT3 signaling pathway could become a potential target for managing DKD.