Atg7 mediates renal tubular cell apoptosis in vancomycin nephrotoxicity through activation of PKC-
Atg7 mediates renal tubular cell apoptosis in vancomycin nephrotoxicity through activation of PKC-
复制标题
Atg7 通过激活 PKC-δ 介导万古霉素肾毒性中肾小管细胞凋亡。
DOI：
10.1096/fj.201801515r
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发表时间：
2019-03-01
期刊：
影响因子：
4.8
通讯作者：
Zhang, Dongshan
中科院分区：
文献类型：
--
作者：
Xu, Xuan;Pan, Jian;Zhang, Dongshan
最近的研究表明，自噬在各种急性肾损伤（阿基）模型中表现出肾脏保护作用。然而，其在万古霉素（货车）诱导的阿基中的作用在很大程度上仍不清楚。这项研究首次表明，自噬在人肾-2细胞和肾组织中被迅速激活，并且在货车处理期间，通过抑制ERK 1/2和mTOR使哺乳动物雷帕霉素靶标（mTOR）失活。有趣的是，对于体外和体内实验，通过氯喹和PT-Atg 7-KO抑制自噬显著改善了Van诱导的肾损伤和肾小管细胞凋亡。整体基因表达分析表明，在PT-Atg 7野生型小鼠的肾皮质组织中，货车处理诱导了6159个基因的表达水平，其中18个基因在PT-Atg 7-KO小鼠中被显著抑制。这18个基因被进一步分类为程序性细胞死亡、蛋白结合、信号转导、E3泛素连接酶、核苷二磷酸激酶活性和E1样激活酶。出乎意料的是，在货车处理后，发现在与细胞死亡相关的4个基因中PKC-表达最高，其在体外和PT-Atg 7-KO小鼠中被显著抑制。此外，Atg 7在货车处理过程中可通过与PKC-结合诱导肾细胞凋亡。同样，PKC的抑制减轻了Van诱导的人肾2细胞和肾组织的凋亡。此外，数据显示PT-Atg 7-KO对Van诱导的肾毒性具有肾保护作用，但在注射myc标记的PKC后，这种作用丧失。总之，这些结果表明货车通过抑制ERK 1/2和mTOR信号通路的激活来诱导自噬。此外，Atg 7通过激活PKC介导Van诱导的阿基。总之，自噬抑制可以作为治疗由货车诱导的肾毒性阿基的新的治疗靶标。Xu，X.，Pan，J.，Li，H.，Li，X.，Fang，F.，吴，D.，Zhou，Y.，（1996年），中国科学院，Zheng，P.，中国地质大学，Xiong，L.，Zhang，L. Atg 7通过激活PKC-1介导万古霉素肾毒性肾小管细胞凋亡。
Recent studies have shown that autophagy exhibits a renoprotective role in various models of acute kidney injury (AKI). However, its role in vancomycin (Van)-induced AKI remains largely unclarified. This study was the first to indicate that autophagy was rapidly activated in both human kidney-2 cells and renal tissues, and mammalian target of rapamycin (mTOR) was inactivated via the suppression of ERK1/2 and mTOR during Van treatment. Interestingly, for both in vitro and in vivo experiments, the suppression of autophagy via chloroquine and PT-Atg7-KO significantly ameliorated Van-induced kidney injury and renal tubular cell apoptosis. Global gene expression analysis indicated that the expression levels of 6159 genes were induced by Van treatment in the kidney cortical tissues of PT-Atg7 wild-type mice, and 18 of them were notably suppressed in PT-Atg7-KO mice. These 18 genes were further classified as programmed cell death, protein binding, signal transduction, E3 ubiquitin ligase, nucleoside diphosphate kinase activity, and E1-like activating enzyme. Unexpectedly, following Van treatment, PKC- expression was found to be highest among the 4 genes related to cell death, which was remarkably suppressed in vitro and in PT-Atg7-KO mice. In addition, Atg7 could induce renal cell apoptosis during Van treatment via binding to PKC-. Likewise, the inhibition of PKC ameliorated Van-induced apoptosis in human kidney-2 cells and kidney tissues. Furthermore, the data showed that PT-Atg7-KO exerted a renoprotective effect against Van-induced nephrotoxicity, but this effect was lost after injection with myc-tagged PKC. Taken altogether, these results indicate that Van induces autophagy by suppressing the activation of the ERK1/2 and mTOR signaling pathway. In addition, Atg7 mediates Van-induced AKI through the activation of PKC. In sum, autophagy inhibition may serve as a novel therapeutic target for treating nephrotoxic AKI induced by Van.Xu, X., Pan, J., Li, H., Li, X., Fang, F., Wu, D., Zhou, Y., Zheng, P., Xiong, L., Zhang, D. Atg7 mediates renal tubular cell apoptosis in vancomycin nephrotoxicity through activation of PKC-.