Genipin attenuates cisplatin-induced nephrotoxicity by counteracting oxidative stress, inflammation, and apoptosis

Cisplatin (CP) is a potent and widely used chemotherapeutic agent. However, the clinical benefits of CP are compromised because it elicits nephrotoxicity and ototoxicity. In this study, we investigated the nephroprotective effects of the phytochemical genipin (GP) isolated from the gardenia (Gardenia jasminoides) fruit, using a murine model of CP-induced nephropathy. GP pretreatment attenuated the CP-induced renal tissue injury by diminishing the serum blood urea nitrogen, creatinine, and cystatin C levels, as well as those of kidney injury molecule-1. In addition, GP attenuated the CP-induced oxidative/nitrative stress by suppressing the activation of NADPH oxidase, augmenting the endogenous antioxidant defense system, and diminishing the accumulation of 4-hydroxynonenal and 3-nitrotyrosine in renal tissues. Furthermore, reduced levels of proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1 beta indicated that CP-induced renal inflammation was mitigated upon the treatment with GP. GP also attenuated the CP-induced activation of mitogen-activated protein kinases, excessive activities of caspase-3/7 and poly(ADP-ribose) polymerase, DNA fragmentation, and apoptosis. When administered 12h after the onset of kidney injury, GP showed a therapeutic effect by ameliorating CP-induced nephrotoxicity. Moreover, GP synergistically enhanced the CP-induced cell death of T24 human bladder cancer cells. Collectively, our data indicate that GP attenuated the CP-induced renal tissue injury by abrogating oxidative/nitrative stress and inflammation and by blocking cell death pathways, thereby improving the renal function. Thus, our results suggest that the use of GP may be a promising new protective strategy against cisplatin-induced nephrotoxicity.