Intervention of mitochondrial activity attenuates cisplatin-induced acute kidney injury
Intervention of mitochondrial activity attenuates cisplatin-induced acute kidney injury
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线粒体活性的干预可减轻顺铂引起的急性肾损伤
DOI：
10.1007/s11255-019-02113-5
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发表时间：
2019
影响因子：
2
通讯作者：
Huang Songming
中科院分区：
文献类型：
--
作者：
Yang Yunwen;Fu Yu;Wang Peipei;Liu Suwen;Sha Yugen;Zhang Yue;Zhang Aihua;Jia Zhanjun;Ding Guixia;Huang Songming
目的顺铂（cisplatin，DDP）可引起线粒体呼吸链功能紊乱，导致活性氧（reactive oxygen species，ROS）的过度产生，进而导致肾损伤。本研究旨在评价线粒体电子传递抑制剂鱼藤酮（线粒体复合物I抑制剂）和嘧菌酯（线粒体复合物III抑制剂）在顺铂诱导的肾损伤中的作用。注射（20 mg/kg）。然后，小鼠在食物中加入或不加入200 ppm鱼藤酮。顺铂给药72 h后处死小鼠。收集血清和肾组织用于进一步分析。在体外，用顺铂（5 μg/mL）和鱼藤酮/嘧菌酯处理小鼠近端肾小管细胞（mPTC）24小时。流式细胞术，Western blotting，TUNEL染色被用来评估细胞injuries.ResultsIn体内，鱼藤酮治疗明显改善顺铂诱导的肾小管损伤证明了改善组织学和阻断NGAL上调。同时，顺铂引起的肾功能不全，表现为血清肌酐（Scr），血尿素氮（BUN）和胱抑素C水平的升高，鱼藤酮治疗显着减少。此外，裂解的caspase-3和转移酶dUTP缺口末端标记（TUNEL）阳性细胞的增量显着减少线衰减的线粒体功能障碍和氧化应激鱼藤酮给药后。在体外，鱼藤酮和嘧菌酯保护线粒体功能障碍，氧化应激，肾小管细胞凋亡诱导cisplatin.ConclusionsOur结果表明，线粒体活性的抑制显着衰减顺铂肾毒性可能通过抑制线粒体氧化应激。
ObjectivesThe 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.MethodsIn 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 µg/mL) and rotenone/azoxystrobin for 24 h. Flow cytometry, Western blotting, and TUNEL staining were used to evaluate the cell injury.ResultsIn 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.ConclusionsOur results demonstrated that inhibition of mitochondrial activity significantly attenuated cisplatin nephrotoxicity possibly by inhibiting mitochondrial oxidative stress.