Dimethyl fumarate ameliorates cisplatin-induced renal tubulointerstitial lesions

Abstract

Dimethyl fumarate (DMF) has an antioxidant effect by activating the nuclear factor erythroid 2-related transcription factor 2 (Nrf2). Cisplatin (CIS) has nephrotoxicity as a frequently associated side effect that is mainly mediated by oxidative stress. In this study, we investigated whether the DMF-mediated antioxidative mechanism activated by Nrf2 can ameliorate CIS-induced renal tubulointerstitial lesions in rats. In Experiments 1 and 2, 25 five-week-old male Wistar rats were divided into five groups: control, CIS, and 3 CIS+DMF groups (300, 1,500, and 7,500 ppm in Experiment 1; 2,000, 4,000, and 6,000 ppm in Experiment 2). Rats were fed their respective DMF-containing diet for 5 weeks. CIS was injected 1 week after starting DMF administration, and the same volume of saline was injected into the control group. CIS-induced severe tubular injury, such as necrosis and degeneration in the outer segment of the outer medulla, was inhibited in the 7,500 ppm DMF group and ameliorated in all DMF groups in Experiment 2. Increased interstitial mononuclear cell infiltration and increased Sirius red-positive areas were also observed in CIS-administered groups, and these increases tended to be dose-dependently inhibited by DMF co-administration in Experiments 1 and 2. The numbers of α-smooth muscle actin (SMA)-positive myofibroblasts, CD68-positive macrophages, and CD3-positive lymphocytes observed in the peritubular area also increased with CIS administration, and these increases were dose-dependently inhibited by DMF co-administration. Moreover, renal cortical mRNA expression of Nrf2-related genes such as NQO1 increased in DMF groups. This investigation showed that DMF ameliorates CIS-induced renal tubular injury via NQO1-mediated antioxidant mechanisms and reduces the consequent tubulointerstitial fibrosis.