Dunnione protects against experimental cisplatin-induced nephrotoxicity by modulating NQO1 and NAD(+) levels

Abstract

Despite being an efficacious anticancer agent, the clinical utility of cisplatin is hindered by its cardinal side effects. This investigation aimed to appraise potential protective impact of dunnione, a natural naphthoquinone pigment with established NQO1 stimulatory effects, on cisplatin nephrotoxicity of rats. Dunnione was administered orally at 10 and 20 mg/kg doses for 4 d and a single injection of cisplatin was delivered at the second day. Renal histopathology, inflammatory/oxidative stress/apoptotic markers, kidney function, and urinary markers of renal injury were assessed. Dunnione repressed cisplatin-induced inflammation in the kidneys as indicated by decreased TNF-alpha/IL-1 beta levels, and reduced nuclear phosphorylated NF-kappa B p65. This agent also obviated cisplatin-invoked oxidative stress as elucidated by decreased MDA/GSH levels and increased SOD/CAT activities. Dunnione, furthermore, improved renal histological deteriorations as well as caspase-3 activities and terminal deoxynucleotidyl transferase (TUNEL) positive cells, the indicators of apoptosis. Moreover, it up-regulated nuclear Nrf2 and cytosolic haeme-oxygenase-1 (HO-1) and NQO1 levels; meanwhile, promoted NAD(+)/NADH ratios followed by enhancing the activities of Sirt1 and PARP1; and further attenuated nuclear acetylated NF-kappa B p65. Dunnione additionally declined cisplatin-evoked retrogression in renal function and upraise in urinary markers of glomerular and tubular injury as demonstrated by decreased serum urea and creatinine with simultaneous reductions in urinary excretions of collagen type IV, podocin, cystatin C, and retinol-binding protein (RBP). Altogether, these findings offer dunnione as a potential protective agent against cisplatin-induced nephrotoxicity in rats.