期刊
FASEB JOURNAL
卷 34, 期 6, 页码 7500-7519出版社
WILEY
DOI: 10.1096/fj.201903038R
关键词
CXCR4; diabetic kidney disease; mitochondria; SDF-1 alpha; sitagliptin; STAT3
资金
- National Natural Science Foundation of China [81670657, 81870504, 81870468, 81400735]
- National Twelfth Five-Year Plan for Science & Technology Support [2013BAI02B01-01]
- Shanghai Jiao Tong University [YG2017MS10]
- Shanghai Municipal Commission of Science and Technology [18DZ2260200]
- Open Project of Shanghai Key Laboratory of Sleep Disordered Breathing [SHKSDB-KF-19-04]
- Science and Technology Commission of Shanghai Municipality [14DZ2260200]
Mitochondrial abnormalities play critical roles in diabetic tubular injury progression. Dipeptidyl peptidase-4 (DPP4) inhibitors are widely used antihyperglycemic agents 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 of DBA2/J (D2) diabetic mice with unilateral nephrectomy and in albumin-stimulated tubular cells. The inhibition of DPP4 by sitagliptin (Sita) 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. Downstream of DPP4, the SDF-1 alpha/CXCR4 pathway was significantly suppressed in diabetic tubules. After Sita treatment, this signaling pathway was restored, and the mitochondrial dynamics was improved. Furthermore, a direct interaction between STAT3 and OPA1 was found in the mitochondria of tubular cells, and this effect was weakened by overloading albumin and by CXCR4 siRNA treatment, suggesting a possible link between DPP4-mediated SDF-1 alpha/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-1 alpha/CXCR4/STAT3 signaling pathway could become a potential target for managing DKD.
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