Pharmacological activation of NQO1 increases NAD(+) levels and attenuates cisplatin-mediated acute kidney injury in mice

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Title
Pharmacological activation of NQO1 increases NAD(+) levels and attenuates cisplatin-mediated acute kidney injury in mice
Author(s)
G S Oh; H J Kim; J H Choi; A Shen; S K Choe; A Karna; S H Lee; H J Jo; S H Yang; T H Kwak; Chul Ho Lee; R Park; H S So
Bibliographic Citation
Kidney International, vol. 85, no. 3, pp. 547-560
Publication Year
2014
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 NAD(P)H: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.
Keyword
cisplatinnephrotoxicityNQO1sirtuins
ISSN
0085-2538
Publisher
Elsevier
DOI
http://dx.doi.org/10.1038/ki.2013.330
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of National Bio-Infrastructure > Laboratory Animal Resource & Research Center > 1. Journal Articles
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