PMID- 31020626 OWN - NLM STAT- MEDLINE DCOM- 20200110 LR - 20200225 IS - 1573-2584 (Electronic) IS - 0301-1623 (Linking) VI - 51 IP - 7 DP - 2019 Jul TI - Intervention of mitochondrial activity attenuates cisplatin-induced acute kidney injury. PG - 1207-1218 LID - 10.1007/s11255-019-02113-5 [doi] AB - OBJECTIVES: The dysfunction of mitochondrial respiratory chain induced by cisplatin results in overproduction of reactive oxygen species (ROS) which contributes to kidney injury. The current study aimed to evaluate the effect of a mitochondrial electron transport inhibitors of rotenone (mitochondrial complex I inhibitor) and azoxystrobin (mitochondrial complex III inhibitor), in cisplatin-induced kidney injury. METHODS: In vivo, cisplatin was administered to male C57BL/6J mice by a single intraperitoneal (i.p.) injection (20 mg/kg). Then the mice were treated with or without 200 ppm rotenone in food. Mice were sacrificed after cisplatin administration for 72 h. The serum and the kidney tissues were collected for further analysis. In vitro, mouse proximal tubular cells (mPTCs) were treated with cisplatin (5 microg/mL) and rotenone/azoxystrobin for 24 h. Flow cytometry, Western blotting, and TUNEL staining were used to evaluate the cell injury. RESULTS: In vivo, rotenone treatment obviously ameliorated cisplatin-induced renal tubular injury evidenced by the improved histology and blocked NGAL upregulation. Meanwhile, cisplatin-induced renal dysfunction shown by the increased levels of serum creatinine (Scr), blood urea nitrogen (BUN), and cystatin C were significantly reduced by rotenone treatment. Moreover, the increments of cleaved caspase-3 and transferase dUTP nick-end labeling (TUNEL)-positive cells were markedly decreased in line with the attenuated mitochondrial dysfunction and oxidative stress after rotenone administration. In vitro, rotenone and azoxystrobin protected against mitochondrial dysfunction, oxidative stress, and renal tubular cell apoptosis induced by cisplatin. CONCLUSIONS: Our results demonstrated that inhibition of mitochondrial activity significantly attenuated cisplatin nephrotoxicity possibly by inhibiting mitochondrial oxidative stress. FAU - Yang, Yunwen AU - Yang Y AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. FAU - Fu, Yu AU - Fu Y AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. FAU - Wang, Peipei AU - Wang P AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. FAU - Liu, Suwen AU - Liu S AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. FAU - Sha, Yugen AU - Sha Y AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. FAU - Zhang, Yue AU - Zhang Y AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. FAU - Zhang, Aihua AU - Zhang A AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. FAU - Jia, Zhanjun AU - Jia Z AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. FAU - Ding, Guixia AU - Ding G AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China. bhgyuan@163.com. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. bhgyuan@163.com. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. bhgyuan@163.com. FAU - Huang, Songming AU - Huang S AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China. smhuang@njmu.edu.cn. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. smhuang@njmu.edu.cn. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. smhuang@njmu.edu.cn. LA - eng PT - Journal Article DEP - 20190424 PL - Netherlands TA - Int Urol Nephrol JT - International urology and nephrology JID - 0262521 RN - 0 (Pyrimidines) RN - 0 (Strobilurins) RN - 0 (Uncoupling Agents) RN - 03L9OT429T (Rotenone) RN - EC 7.1.1.8 (Electron Transport Complex III) RN - NYH7Y08IPM (azoxystrobin) RN - Q20Q21Q62J (Cisplatin) SB - IM MH - *Acute Kidney Injury/chemically induced/metabolism/pathology/prevention & control MH - Animals MH - Cisplatin/*pharmacology MH - Electron Transport Complex III/antagonists & inhibitors MH - Kidney/metabolism/pathology MH - Kidney Function Tests/methods MH - Mice MH - Mice, Inbred C57BL MH - *Mitochondria/drug effects/metabolism MH - Oxidative Stress/drug effects MH - Pyrimidines/*pharmacology MH - Rotenone/*pharmacology MH - Strobilurins/*pharmacology MH - Treatment Outcome MH - Uncoupling Agents/pharmacology OTO - NOTNLM OT - AKI OT - Cisplatin OT - Mitochondrial activity OT - Oxidative stress EDAT- 2019/04/26 06:00 MHDA- 2020/01/11 06:00 CRDT- 2019/04/26 06:00 PHST- 2018/11/15 00:00 [received] PHST- 2019/02/18 00:00 [accepted] PHST- 2019/04/26 06:00 [pubmed] PHST- 2020/01/11 06:00 [medline] PHST- 2019/04/26 06:00 [entrez] AID - 10.1007/s11255-019-02113-5 [pii] AID - 10.1007/s11255-019-02113-5 [doi] PST - ppublish SO - Int Urol Nephrol. 2019 Jul;51(7):1207-1218. doi: 10.1007/s11255-019-02113-5. Epub 2019 Apr 24.