PMID- 30589566 OWN - NLM STAT- MEDLINE DCOM- 20200511 LR - 20231213 IS - 1530-6860 (Electronic) IS - 0892-6638 (Linking) VI - 33 IP - 3 DP - 2019 Mar TI - Atg7 mediates renal tubular cell apoptosis in vancomycin nephrotoxicity through activation of PKC-delta. PG - 4513-4524 LID - 10.1096/fj.201801515R [doi] AB - 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-delta 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-delta. Likewise, the inhibition of PKCdelta 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 PKCdelta. 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 PKCdelta. 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-delta. FAU - Xu, Xuan AU - Xu X AD - Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, China. FAU - Pan, Jian AU - Pan J AD - Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, China. FAU - Li, Huiling AU - Li H AD - Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, China. FAU - Li, Xiaozhou AU - Li X AD - Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, China. FAU - Fang, Fang AU - Fang F AD - Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, China. FAU - Wu, Dengke AU - Wu D AD - Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, China. FAU - Zhou, Yu AU - Zhou Y AD - Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, China. FAU - Zheng, Peiling AU - Zheng P AD - Department of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, Changsha, China; and. FAU - Xiong, Li AU - Xiong L AD - Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, China. FAU - Zhang, Dongshan AU - Zhang D AD - Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181227 PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (Atg7 protein, mouse) RN - 6Q205EH1VU (Vancomycin) RN - EC 2.7.1.- (Prkcd protein, mouse) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.13 (PRKCD protein, human) RN - EC 2.7.11.13 (Protein Kinase C-delta) RN - EC 6.2.1.45 (ATG7 protein, human) RN - EC 6.2.1.45 (Autophagy-Related Protein 7) SB - IM EIN - FASEB J. 2019 Aug;33(8):9695. PMID: 31361550 MH - Acute Kidney Injury/*chemically induced/metabolism/pathology MH - Animals MH - Apoptosis/drug effects/*physiology MH - Autophagy/drug effects/*physiology MH - Autophagy-Related Protein 7/antagonists & inhibitors/deficiency/genetics/*physiology MH - Cell Line MH - Enzyme Activation/drug effects MH - Gene Expression Profiling MH - Gene Ontology MH - Humans MH - Kidney Tubules/*drug effects/metabolism/pathology MH - MAP Kinase Signaling System/drug effects MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Protein Binding MH - Protein Kinase C-delta/*physiology MH - TOR Serine-Threonine Kinases/metabolism MH - Vancomycin/*toxicity OTO - NOTNLM OT - ERK1/2 OT - apoptosis OT - autophagy OT - mTOR OT - vancomycin EDAT- 2018/12/28 06:00 MHDA- 2020/05/12 06:00 CRDT- 2018/12/28 06:00 PHST- 2018/12/28 06:00 [pubmed] PHST- 2020/05/12 06:00 [medline] PHST- 2018/12/28 06:00 [entrez] AID - 10.1096/fj.201801515R [doi] PST - ppublish SO - FASEB J. 2019 Mar;33(3):4513-4524. doi: 10.1096/fj.201801515R. Epub 2018 Dec 27.