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.

Mechanisms of Cisplatin-Induced Acute Kidney Injury: Pathological Mechanisms, Pharmacological Interventions, and Genetic Mitigations

“…SA and cisplatin-treated rats showed elevation in these key antioxidants indicating an enhanced antioxidant defense system following SA treatment [ 103 ]. Pharmacologically, it has been demonstrated that activation of the Nrf2 signaling pathway by N,N-dimethylformamide (DMF) following cisplatin treatment attenuated AKI [ 102 ], as well as tubulointerstitial lesions [ 106 ]. Both ameliorating effects are associated with stimulation of antioxidants such as HO-1 and NAD(P)H quinone oxidoreductase 1 (NQO1) [ 102 , 106 ].…”

“…Pharmacologically, it has been demonstrated that activation of the Nrf2 signaling pathway by N,N-dimethylformamide (DMF) following cisplatin treatment attenuated AKI [ 102 ], as well as tubulointerstitial lesions [ 106 ]. Both ameliorating effects are associated with stimulation of antioxidants such as HO-1 and NAD(P)H quinone oxidoreductase 1 (NQO1) [ 102 , 106 ]. Stimulation of these two antioxidants was observed in mice treated with Isoorientin a flavone, suggested to activate the Nrf2 signaling cascade [ 44 ].…”

Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

“…In addition, fumarate seems to have protective effects in the kidney, as demonstrated in kidney damage induced by ciclosporin, cisplatin, folic acid, and I/R [ 143 , 144 , 145 ], in which dimethyl fumarate administration reduce kidney damage by enhancing the antioxidant response driven by Nrf2 ( Figure 2 g). Moreover, dimethyl fumarate is already approved by the food and drug administration (FDA) as an immunomodulatory drug for the therapeutic management of multiple sclerosis [ 146 ].…”

Protective Role of Nrf2 in Renal Disease

“…Bardoxolone reduced fibrosis through the Nrf2/Smad7 axis, inhibiting the TGF-β/Smad signaling, and ameliorating aristolochic acid-induced AKI [ 183 ]. In cisplatin-AKI, DMF also reduced peritubular fibrosis [ 184 ]. In a mouse model of folic acid-induced AKI, specific deletion of GSK3β in renal tubules or treatment with a GSK3β inhibitor improved the Nrf2 antioxidant response, independently of Keap1, protecting from AKI to CKD transition [ 185 ].…”