TRPM2 protects against cisplatin-induced acute kidney injury and mitochondrial dysfunction via modulating autophagy #MMPMID37649595
Yu B; Jin L; Yao X; Zhang Y; Zhang G; Wang F; Su X; Fang Q; Xiao L; Yang Y; Jiang LH; Chen J; Yang W; Lin W; Han F
Theranostics 2023[]; 13 (13): 4356-4375 PMID37649595show ga
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.
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Theranostics 2023 ; 13 (13): 4356-4375
