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 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.

β-Lapachone enhances Mre11-Rad50-Nbs1 complex expression in cisplatin-induced nephrotoxicity

“…increasing NAD + ; this leads attenuation of cisplatin-induced 202 nephrotoxicity [13]. These findings are in line with the results 203 obtained in the present study.…”

“…tin's antitumor activity [13]. However, to the best of the authors' 54 knowledge, the effect of b-lapachone on MRN complex expression 55…”

Renoprotective approaches and strategies in acute kidney injury

“…Moreover, recent studies have begun to test comorbid models. For example, cisplatin nephrotoxicity has been investigated in tumor-bearing animal models (Pabla et al, 2011; Oh et al, 2014). and ischemic AKI examined in diabetic animals (Kelly et al, 2009; Peng et al, 2015; Gao et al, 2013).…”

Co‐culture of bone marrow‐derived mesenchymal stem cells overexpressing lipocalin 2 with HK‐2 and HEK293 cells protects the kidney cells against cisplatin‐induced injury

“…Although we are not sure that cisplatin treatment is a good model of kidney injury in the clinical situation, several in vitro and in vivo studies use cisplatin treatment as a model of kidney injury (Han and Chesney, 2009;Miller et al, 2010;Kanki et al, 2014;Fukasawa et al, 2014;Oh et al, 2014). We find that co-culture of MSC-Lcn2 with the two kidney cells following their exposure to cisplatin resulted in their protection against cisplatin-induced cytotoxicity and apoptosis, in addition to upregulation of some growth factors and antioxidants in the kidney cells.…”