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Intervention of mitochondrial activity attenuates cisplatin-induced acute kidney injury

  • Nephrology - Original Paper
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Abstract

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 µg/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.

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Acknowledgements

This work was supported by Grants from the National Natural Science Foundation of China (Nos. 81670678, 81830020, 81873599, 81530023, 81770690, 81700642, 81670647, and 81570616), the National Key Research and Development Program (No. 2016YFC0906103), and the Natural Science Foundation of Jiangsu Province (No. BK20170150).

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Authors and Affiliations

  1. Department of Nephrology, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China

    Yunwen Yang, Yu Fu, Peipei Wang, Suwen Liu, Yugen Sha, Yue Zhang, Aihua Zhang, Zhanjun Jia, Guixia Ding & Songming Huang

  2. Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China

    Yunwen Yang, Yu Fu, Peipei Wang, Suwen Liu, Yugen Sha, Yue Zhang, Aihua Zhang, Zhanjun Jia, Guixia Ding & Songming Huang

  3. Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, 210008, China

    Yunwen Yang, Yu Fu, Peipei Wang, Suwen Liu, Yugen Sha, Yue Zhang, Aihua Zhang, Zhanjun Jia, Guixia Ding & Songming Huang

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  1. Yunwen Yang
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Correspondence to Guixia Ding or Songming Huang.

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All animal experiments were performed according to protocols approved by the Institutional Animal Care and Use Committee of Nanjing Medical University (IACUC 14030112-2).

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Yang, Y., Fu, Y., Wang, P. et al. Intervention of mitochondrial activity attenuates cisplatin-induced acute kidney injury. Int Urol Nephrol 51, 1207–1218 (2019). https://doi.org/10.1007/s11255-019-02113-5

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