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

Abstract

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. 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. 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. 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.