TRPM2 protects against cisplatin-induced acute kidney injury and mitochondrial dysfunction via modulating autophagy

Background: Cisplatin is a widely used anti-tumor agent but its use is frequently limited by nephrotoxicity. Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel which is generally viewed as a sensor of oxidative stress, and increasing evidence supports its link with a...

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Published in:Theranostics 2023-01, Vol.13 (13), p.4356-4375
Main Authors: Yu, Binfeng, Jin, Lini, Yao, Xi, Zhang, Yi, Zhang, Gensheng, Wang, Fangqin, Su, Xinwan, Fang, Qiuyuan, Xiao, Liang, Yang, Yi, Jiang, Lin-Hua, Chen, Jianghua, Yang, Wei, Lin, Weiqiang, Han, Fei
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Language:English
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Research Paper
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Summary:Background: Cisplatin is a widely used anti-tumor agent but its use is frequently limited by nephrotoxicity. Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel which is generally viewed as a sensor of oxidative stress, and increasing evidence supports its link with autophagy, a critical process for organelle homeostasis. Methods: Cisplatin-induced cell injury and mitochondrial damage were both assessed in WT and Trpm2- knockout mice and primary cells. RNA sequencing, immunofluorescence staining, immunoblotting and flowcytometry were applied to interpret the mechanism of TRPM2 in cisplatin nephrotoxicity. Results: Knockout of TRPM2 exacerbates renal dysfunction, tubular injury and cell apoptosis in a model of acute kidney injury (AKI) induced by treatment with cisplatin. Cisplatin-caused tubular mitochondrial damage is aggravated in TRPM2-deficient mice and cells and, conversely, alleviated by treatment with Mito-TEMPO, a mitochondrial ROS scavenger. TRPM2 deficiency hinders cisplatin-induced autophagy via blockage of Ca 2+ influx and subsequent up-regulation of AKT-mTOR signaling. Consistently, cisplatin-induced tubular mitochondrial damage, cell apoptosis and renal dysfunction in TRPM2-deficient mice are mitigated by treatment with a mTOR inhibitor. Conclusion: Our results suggest that the TRPM2 channel plays a protective role in cisplatin-induced AKI via modulating the Ca 2+ -AKT-mTOR signaling pathway and autophagy, providing novel insights into the pathogenesis of kidney injury.
ISSN:1838-7640
1838-7640
DOI:10.7150/thno.84655