title: NQO1 Deficiency Leads Enhanced Autophagy in Cisplatin-Induced Acute Kidney Injury Through the AMPK/TSC2/mTOR Signaling Pathway.
abstract: Recent studies have revealed that autophagy is induced under various disease conditions; however, the role of autophagy in pathological states is controversial.
  
  
  
  quinone oxidoreductase 1 (NQO1) is a highly inducible cytoprotective gene that regulates reactive oxygen species (ROS) generation. In this study, we examined whether NQO1 deficiency affects the autophagy process in response to cisplatin-induced nephrotoxicity.
  
  
  
  In vitro, NQO1 and autophagy-associated proteins were induced after cisplatin treatment and the autophagosomes markedly increased in the cisplatin-treated NQO1-knockdown ACHN cells together with increased ROS production. In vivo, NQO1-KO mice displayed a significant increase in cisplatin-induced acute kidney injury (AKI), as indicated by elevated tubular damage and apoptosis as well as by suppressed cytoprotective signals. In agreement with the in vitro findings, NQO1-KO cisplatin-treated mice displayed a notable increase in autophagy-associated protein expression compared with their wild-type counterparts. Meanwhile, the expression of Ras-related protein 7, which participates in autophagosome maturation and lysosome fusion, markedly decreased in NQO1-KO mice, indicating hampered progress in late autophagy, and was accompanied by increased p62 protein expression. Moreover, NQO1 deletion enhanced the effect of the mammalian target of the rapamycin inhibitor, rapamycin, and led to enhanced tuberous sclerosis complex 2 phosphorylation through AMP-activated protein kinase activation.
  
  
  
  These results indicate that autophagy may be enhanced to counter the increased stress due to NQO1 deficiency, an oxidative stress barrier. The present results demonstrate the significant influence of NQO1 on the autophagy process and support the hypothesis that autophagy plays a protective role under oxidative stress conditions. Antioxid. Redox Signal. 24, 867-883.
authors.affiliation: 1 Department of Veterinary Medicine, Institute of Veterinary Science, Chungnam National University , Daejeon, Republic of Korea.
authors.forename: Tae-Won
authors.initials: TW
authors.lastname: Kim
authors.affiliation: 1 Department of Veterinary Medicine, Institute of Veterinary Science, Chungnam National University , Daejeon, Republic of Korea.
authors.forename: Young-Jung
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: 1 Department of Veterinary Medicine, Institute of Veterinary Science, Chungnam National University , Daejeon, Republic of Korea.
authors.forename: Hyun-Tae
authors.initials: HT
authors.lastname: Kim
authors.affiliation: 1 Department of Veterinary Medicine, Institute of Veterinary Science, Chungnam National University , Daejeon, Republic of Korea.
authors.forename: Se-Ra
authors.initials: SR
authors.lastname: Park
authors.affiliation: 2 Herbal Medicine Formulation Research Group, Korea Institute of Oriental Medicine , Daejeon, Republic of Korea.
authors.forename: Mee-Young
authors.initials: MY
authors.lastname: Lee
authors.affiliation: 3 Department of Biomedical Science, Youngdong University , Yeongdong, Republic of Korea.
authors.forename: Yong-Deok
authors.initials: YD
authors.lastname: Park
authors.affiliation: 4 Laboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology , Daejeon, Republic of Korea.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: 1 Department of Veterinary Medicine, Institute of Veterinary Science, Chungnam National University , Daejeon, Republic of Korea.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Jung
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000201:enzymology; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000633:toxicity*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000263:Adenylate Kinase; D000970:Antineoplastic Agents; D002945:Cisplatin; D008869:Microtubule-Associated Proteins; D016660:NAD(P)H Dehydrogenase (Quinone); D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C526109:Anxa3 protein, rat; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; C491732:Nqo1 protein, mouse; C546843:mTOR protein, mouse