TRPM2 protects against cisplatin-induced acute kidney injury and mitochondrial dysfunction via modulating autophagy.
TRPM2 protects against cisplatin-induced acute kidney injury and mitochondrial dysfunction via modulating autophagy.
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TRPM2通过调节自噬保护顺铂诱导的急性肾损伤和线粒体功能障碍。
作者：
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
背景：顺铂是一种广泛使用的抗肿瘤药物，但其使用经常受到肾毒性的限制。瞬时受体电位melastatin 2（TRPM 2）是一种非选择性的阳离子通道，被认为是氧化应激的传感器，越来越多的证据支持其与细胞器自噬的联系。方法：在WT和Trpm 2基因敲除小鼠和原代细胞中评估顺铂诱导的细胞损伤和线粒体损伤。采用RNA测序、免疫荧光染色、免疫印迹和流式细胞术等方法研究TRPM 2在顺铂肾毒性中的作用机制。结果如下：TRPM 2基因敲除在顺铂治疗诱导的急性肾损伤（阿基）模型中加重肾功能不全、肾小管损伤和细胞凋亡。顺铂引起的肾小管线粒体损伤在TRPM 2缺陷型小鼠和细胞中加重，相反，通过线粒体ROS清除剂Mito-TEMPO治疗减轻。TRPM 2缺陷通过阻断Ca 2+内流和随后上调AKT-mTOR信号传导来阻碍顺铂诱导的自噬。一致的是，顺铂诱导的肾小管线粒体损伤，细胞凋亡和TRPM 2缺陷型小鼠肾功能不全减轻了治疗与mTOR抑制剂。结论：我们的研究结果表明，TRPM 2通道通过调节Ca 2 +-AKT-mTOR信号通路和自噬在顺铂诱导的阿基中起保护作用，为肾损伤的发病机制提供了新的见解。
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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影响因子：
21.3
作者：
通讯作者：
--
影响因子：
5.6
作者：
Huo, Yanan;Chen, Wei;Jin, Xiuming
通讯作者：
Jin, Xiuming
影响因子：
4.8
作者：
Chen, Shu-jen;Hoffman, Nicholas E.;Miller, Barbara A.
通讯作者：
Miller, Barbara A.
DOI：
10.1152/ajpcell.00098.2018
发表时间：
2018-10-01
期刊：
American journal of physiology. Cell physiology
影响因子：
--
作者：
Hirschler-Laszkiewicz I;Chen SJ;Bao L;Wang J;Zhang XQ;Shanmughapriya S;Keefer K;Madesh M;Cheung JY;Miller BA
通讯作者：
Miller BA
影响因子：
7.3
作者：
Abuarab, Nada;Munsey, Tim S.;Sivaprasadarao, Asipu
通讯作者：
Sivaprasadarao, Asipu