Sitagliptin Ameliorates Renal Tubular Injury in Diabetic Kidney Disease <i>via</i> STAT3-Dependent Mitochondrial Homeostasis Through SDF-1α/CXCR4 Pathway

Abstract

Background: Mitochondrial abnormalities play critical roles in diabetic tubular injury progression. Dipeptidyl peptidase-4 (DPP4) inhibitors are widely used antihyperglycaemic agents that exert renal protective and positive effects against mitochondrial dysfunction in diabetic kidney disease (DKD). Methods: We examined whether DPP4 inhibitor sitagliptin ameliorate mitochondrial altered fusion-fission processes and fragmentation in the tubules of diabetic mice and albumin-overloaded tubular cells. The possible role of sitagliptin-mediated SDF-1α/CXCR4 signalling and mitochondrial STAT3 in protecting against mitochondrial abnormalities was also studied. Findings: DPP4 upregulation, accompanied by mitochondrial fragmentation and altered mitochondrial dynamic protein expressions, were observed in the tubules of DBA2/J (D2) diabetic mice with unilateral nephrectomy and in albumin-stimulated tubular cells. Sitagliptin ameliorated these mitochondrial perturbations both in vivo and in vitro, whereas DPP4 overexpression aggravated mitochondrial fusion-fission disorder and tubular cell injury in albumin-treated HK-2 cells. DPP4 downstream SDF-1α/CXCR4 pathway was significantly suppressed in diabetic tubules, which was restored after sitagliptin treatment. Furthermore, a direct interaction between STAT3 and OPA1 was found in mitochondria in tubular cells, and this effect was weakened by overloaded albumin and CXCR4 siRNA, suggesting a possible link between DPP4-mediated SDF-1α/CXCR4/STAT3 signalling and mitochondrial dysfunction in diabetic tubular cells. Interpretation: The results suggest a novel mechanism linking the DPP4 enzyme to impaired mitochondrial dynamics homeostasis during tubular injury in DKD and highlight that the SDF-1α/CXCR4/STAT3 signalling pathway could become a potential target for managing DKD. Funding Statement: This study was supported by National Nature Science Foundation of China (81670657,81870504,81870468,81400735), National “Twelfth Five-Year” Plan for Science & Technology Support (2013BAI02B01-01), Medical and Engineering Cross funding of Shanghai Jiao Tong University (YG2017MS10), Shanghai Municipal Commission of Science and Technology (Grant No.18DZ2260200), Open Project of Shanghai Key Laboratory of Sleep Disordered Breathing (SHKSDB-KF-19-04), Science and Technology Commission of Shanghai Municipality (14DZ2260200, the project of Shanghai Key Laboratory of Kidney and Blood Purification). Declaration of Interests: No potential conflicts of interest relevant to this article are reported. Ethics Approval Statement: All animal procedures used in this study were approved by the Animal Care and Use Committee of Shanghai Jiao Tong University.