Atg7 mediates renal tubular cell apoptosis in vancomycin nephrotoxicity through activation of PKC‐δ. Issue 3 (27th December 2018)

• Record Type: Journal Article
• Authors: Xu, Xuan; Pan, Jian; Li, Huiling; Li, Xiaozhou; Fang, Fang; Wu, Dengke; Zhou, Yu; Zheng, Peiling; Xiong, Li; Zhang, Dongshan
• Is Part Of: FASEB journal. Volume 33:Issue 3(2019)
• Page Start: 4513
• Page End: 4524
• Publication Date: 2018-12-27
• Subjects: vancomycin -- autophagy -- apoptosis -- ERK1/2 -- mTOR; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.201801515R
• Languages: English
• ISSNs: 0892-6638

Abstract

ABSTRACT: 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‐δ 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‐δ. Likewise, the inhibition of PKCδ 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 PKCδ. 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 PKCδ. 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‐δ. FASEB J. 33, 4513–4524 (2019). www.fasebj.org