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Dipeptidyl peptidase\u20104 (DPP4) inhibitors are widely used antihyperglycemic\u00a0agents 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\u2010associated protein expression were observed in the tubules of\u00a0DBA2\/J (D2) diabetic mice with unilateral nephrectomy and in albumin\u2010stimulated tubular cells. The inhibition of DPP4 by sitagliptin\u00a0(Sita) ameliorated these mitochondrial perturbations both\u00a0in vivo\n                    <jats:italic>\u00a0<\/jats:italic>\n                    and\n                    <jats:italic>\u00a0<\/jats:italic>\n                    in vitro\n                    <jats:italic>,<\/jats:italic>\n                    whereas DPP4 overexpression aggravated mitochondrial fusion\u2010fission disorder and tubular cell injury in albumin\u2010treated HK\u20102 cells. Downstream of DPP4,\u00a0the SDF\u20101\u03b1\/CXCR4 pathway was significantly suppressed in diabetic tubules. After Sita\u00a0treatment, this signaling pathway was restored, and the\u00a0mitochondrial dynamics was improved. Furthermore, a direct interaction between STAT3 and OPA1 was found in\u00a0the mitochondria of\u00a0tubular cells, and this effect was weakened by overloading albumin and\u00a0by CXCR4 siRNA treatment, suggesting a possible link between DPP4\u2010mediated SDF\u20101\u03b1\/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\u20101\u03b1\/CXCR4\/STAT3 signaling pathway could become a potential target for managing DKD.\n                  <\/jats:p>","DOI":"10.1096\/fj.201903038r","type":"journal-article","created":{"date-parts":[[2020,4,13]],"date-time":"2020-04-13T01:55:49Z","timestamp":1586742949000},"page":"7500-7519","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Sitagliptin ameliorates renal tubular injury in diabetic kidney disease via STAT3\u2010dependent mitochondrial homeostasis through SDF\u20101\u03b1\/CXCR4 pathway"],"prefix":"10.1096","volume":"34","author":[{"given":"Qunzi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Nephrology Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai 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