title: Deletion of NAD(P)H:quinone oxidoreductase 1 represses Mre11-Rad50-Nbs1 complex protein expression in cisplatin-induced nephrotoxicity.
abstract: The Mre11, Rad50, and Nbs1 (MRN) complex is a DNA double-strand break sensor involved in DNA damage repair. Herein, we explored whether deletion of
  quinone oxidoreductase 1 (NQO1), a cytoprotective gene, affected MRN complex expression in the kidney after cisplatin-induced acute kidney injury (AKI). In vitro, cisplatin increased the expression of MRN complex proteins and NQO1 in NQO1-expressing ACHN cells in a time- and concentration-dependent manner. The expression of MRN complex proteins was relatively inhibited in NQO1-knockdown cells. In vivo, increased expression of renal MRN complex proteins was accompanied by upregulation of γ-H2A histone member X, a DNA damage marker, in cisplatin-treated wild-type mice. Although the NQO1-knockout (NQO1(-/-)) mice showed more severe cisplatin-induced renal damage, the renal expression of MRN complex proteins was lower than in NQO1-expressing mice; expression of poly[ADP-ribose] polymerase 1, which promotes MRN complex accumulation, was also lower in these animals. In addition, cisplatin-induced expression of DNA damage repair-related proteins, ataxia telangiectasia mutated and sirtuin1, markedly decreased in the NQO1(-/-) group, relative to the NQO1-expressing mice. These findings suggest that NQO1 deletion might be associated with decreased MRN complex expression, which might be partially responsible for the exacerbation of cisplatin-induced AKI in the absence of NQO1.
authors.affiliation: Department of Veterinary Medicine & Institute of Veterinary Science, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Young-Jung
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Veterinary Medicine & Institute of Veterinary Science, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Tae-Won
authors.initials: TW
authors.lastname: Kim
authors.affiliation: Department of Veterinary Medicine & Institute of Veterinary Science, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: So-Ra
authors.initials: SR
authors.lastname: Park
authors.affiliation: Department of Veterinary Medicine & Institute of Veterinary Science, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Hyun-Tae
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Department of Veterinary Medicine & Institute of Veterinary Science, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Da-Young
authors.initials: DY
authors.lastname: Jung
authors.affiliation: Department of Veterinary Medicine & Institute of Veterinary Science, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Si-Yun
authors.initials: SY
authors.lastname: Ryu
authors.affiliation: Department of Veterinary Medicine & Institute of Veterinary Science, Chungnam National University, Daejeon 305-764, Republic of Korea. Electronic address: jyjung@cnu.ac.kr.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Jung
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D017766:Acid Anhydride Hydrolases; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D063185:Epigenetic Repression; D017353:Gene Deletion; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D000076228:MRE11 Homologue Protein; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C512689:Mre11a protein, mouse; C112156:NBN protein, human; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C000597536:Noq1 protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D000076228:MRE11 Homologue Protein; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; C495198:Rad50 protein, mouse; D045643:DNA Repair Enzymes; D002945:Cisplatin
keywords: Cisplatin; DNA damage; Mre11-Rad50-Nbs1 complex; NAD(P)H:quinone oxidoreductase 1; Nephrotoxicity; Sirtuin1