自噬
TRPM2型
顺铂
PI3K/AKT/mTOR通路
肾毒性
癌症研究
蛋白激酶B
急性肾损伤
线粒体
细胞凋亡
程序性细胞死亡
药理学
氧化应激
化学
肾
细胞生物学
医学
生物
瞬时受体电位通道
内分泌学
内科学
受体
生物化学
化疗
作者
Binfeng Yu,Luhong Jin,Xi Yao,Yi Zhang,Gensheng Zhang,Fangqin Wang,Xinwan Su,Qiuyuan Fang,Xiao Liang,Yi Yang,Linhua Jiang,Jianghua Chen,Wei Yang,Weiqiang Lin,Fangfang Han
出处
期刊:Theranostics
[Ivyspring International Publisher]
日期:2023-01-01
卷期号:13 (13): 4356-4375
摘要
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 Ca2+ 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 Ca2+-AKT-mTOR signaling pathway and autophagy, providing novel insights into the pathogenesis of kidney injury.
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