title: β-Lapachone enhances Mre11-Rad50-Nbs1 complex expression in cisplatin-induced nephrotoxicity.
abstract: BACKGROUND
  Recent studies suggest a potential involvement of the Mre11-Rad50-Nbs1 (MRN) complex, a DNA double-strand breaks (DSBs) sensor, in the development of nephrotoxicity following cisplatin administration. β-Lapachone is a topoisomerase I inhibitor known to reduce cisplatin-induced nephrotoxicity. In this study, by assessing MRN complex expression, we explored whether β-lapachone was involved in DNA damage response in the context of cisplatin-induced nephrotoxicity.
  
  
  METHODS
  Male Balb/c mice were randomly allocated to 4 groups: control, β-lapachone alone, cisplatin alone, and β-lapachone+cisplatin. β-Lapachone was administered with the diet (0.066%) for 2 weeks prior to cisplatin injection (18mg/kg). All mice were sacrificed 3 days after cisplatin treatment.
  
  
  RESULTS
  In the cisplatin-alone group, renal function was disrupted and MRN complex expression increased. As expected, β-lapachone co-treatment attenuated cisplatin-induced pathologic alterations. Notably, although β-lapachone markedly decreased cisplatin-induced renal cell apoptosis and DSBs formation, the β-lapachone+cisplatin group showed the highest MRN complex expression. Moreover, β-lapachone treatment increased the basal expression level of the MRN complex, which was accompanied by enhanced basal expression of SIRTuin1, which is known to regulate Nbs1 acetylation.
  
  
  CONCLUSIONS
  Although, it remains unclear how β-lapachone induces MRN complex expression, our findings suggest that β-lapachone might affect MRN complex expression and participate in DNA damage recovery in cisplatin-induced nephrotoxicity.
authors.affiliation: 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: 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: 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: 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: Department of Veterinary Medicine & Institute of Veterinary Science, Chungnam National University, Daejeon, 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 / Q000096:biosynthesis*; D017766:Acid Anhydride Hydrolases; D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D002945:Cisplatin / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D045643:DNA Repair Enzymes / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D000076228:MRE11 Homologue Protein; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009285:Naphthoquinones / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000096:biosynthesis*; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; D009285:Naphthoquinones; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D059004:Topoisomerase I Inhibitors; C014638:beta-lapachone; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C495198:Rad50 protein, mouse; D045643:DNA Repair Enzymes; D002945:Cisplatin
keywords: DNA damage; NAD(P)H:quinone oxidoreductase 1; Nephrotoxicity; SIRTuin1; β-Lapachone