title: Pharmacological activation of NQO1 increases NAD⁺ levels and attenuates cisplatin-mediated acute kidney injury in mice.
abstract: Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors. In addition to its antitumor activity, cisplatin affects normal cells and may induce adverse effects, such as ototoxicity, nephrotoxicity, and neuropathy. Various mechanisms, such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammatory responses, are critically involved in cisplatin-induced adverse effects. As NAD(+) is a cofactor for various enzymes associated with cellular homeostasis, we studied the effects of increased NAD(+) levels by means of
  quinone oxidoreductase 1 (NQO1) activation using a known pharmacological activator (β-lapachone) in wild-type and NQO1(-/-) mice on cisplatin-induced renal dysfunction in vivo. The intracellular NAD(+)/NADH ratio in renal tissues was significantly increased in wild-type mice co-treated with cisplatin and β-lapachone compared with the ratio in mice treated with cisplatin alone. Inflammatory cytokines and biochemical markers for renal damage were significantly attenuated by β-lapachone co-treatment compared with those in the cisplatin alone group. Notably, the protective effects of β-lapachone in wild-type mice were completely abrogated in NQO1(-/-) mice. Moreover, β-lapachone enhanced the tumoricidal action of cisplatin in a xenograft tumor model. Thus, intracellular regulation of NAD(+) levels through NQO1 activation might be a promising therapeutic target for the protection of cisplatin-induced acute kidney injury.
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Iksan, Republic of Korea.
authors.forename: Gi-Su
authors.initials: GS
authors.lastname: Oh
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Iksan, Republic of Korea.
authors.forename: Hyung-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Iksan, Republic of Korea.
authors.forename: Jae-Hyuck
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Iksan, Republic of Korea.
authors.forename: Aihua
authors.initials: A
authors.lastname: Shen
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Iksan, Republic of Korea.
authors.forename: Seong-Kyu
authors.initials: SK
authors.lastname: Choe
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Iksan, Republic of Korea.
authors.forename: Anzani
authors.initials: A
authors.lastname: Karna
authors.affiliation: Life Science Research Center, KT&G Life Sciences, Suwon, Republic of Korea.
authors.forename: Seung Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Pathology, Kunsan Medical Center of Wonkwang University Hospital, Kunsan, Republic of Korea.
authors.forename: Hyang-Jeong
authors.initials: HJ
authors.lastname: Jo
authors.affiliation: Department of Internal Medicine, Wonkwang University School of Medicine, Iksan, Republic of Korea.
authors.forename: Sei-Hoon
authors.initials: SH
authors.lastname: Yang
authors.affiliation: Life Science Research Center, KT&G Life Sciences, Suwon, Republic of Korea.
authors.forename: Tae Hwan
authors.initials: TH
authors.lastname: Kwak
authors.affiliation: Laboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Iksan, Republic of Korea.
authors.forename: Raekil
authors.initials: R
authors.lastname: Park
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Iksan, Republic of Korea.
authors.forename: Hong-Seob
authors.initials: HS
authors.lastname: So
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D008810:Mice, Inbred C57BL; D009243:NAD / Q000032:analysis*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000502:physiology*; D009285:Naphthoquinones / Q000494:pharmacology; D056564:Sirtuin 1 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; D051996:Transcription Factor RelA; D009243:NAD; C014638:beta-lapachone; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D002945:Cisplatin
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