Dimethyl Fumarate Attenuates Di-(2-Ethylhexyl) Phthalate-Induced Nephrotoxicity Through the Nrf2/HO-1 and NF-κB Signaling Pathways

This study aimed to clarify the nephroprotective effect of dimethyl fumarate (DMF) against Di (2-ethylhexyl) phthalate (DEHP)-induced nephrotoxicity in both in vitro and in vivo models. The HEK-293 cells were exposed to different concentrations of DMF plus IC50 concentration of monoethylhexyl phthalate (MEHP) (the main metabolite of DEHP). Then, some of the oxidative stress parameters including ROS, MDA, and GSH, and cytotoxicity (MTT assay) were determined in treated cells. For in vivo evaluation, rats were divided into 7 groups ( n = 6 per group). Corn oil group (gavage), DEHP group (200 mg/kg dissolved in corn oil, gavage), DMF (15, 30, and 60 mg/kg, gavage) plus DEHP (200 mg/kg) groups, DMF (60 mg/kg, gavage) alone, and vitamin E (20 mg/kg, intraperitoneal (IP)) plus DEHP (200 mg/kg) group. This treatment continued for 45 days. Then, BUN and creatinine were evaluated by a commercial kit based on the urease enzymatic method and the Jaffe method, respectively. Mitochondrial oxidative stress and mitochondrial dysfunction parameters were evaluated using appropriate reagents, and gene expression of the p65 nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNFα), nuclear factor E2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) were evaluated by real-time PCR method. High concentrations of DMF significantly increased cell viability, and GSH content and significantly decreased ROS and MDA levels compared with the MEHP group in HEK-293 cells. DMF (60 mg/kg) significantly decreased BUN and creatinine levels compared with the DEHP group. Mitochondrial function and mitochondrial swelling were significantly improved in DMF group (60 mg/kg) compared with the DEHP group. DMF (30 and 60 mg/kg) significantly improved MMP collapse compared with the DEHP group. DMF (30 and 60 mg/kg) significantly decreased ROS levels compared with the DEHP group in isolated kidney mitochondria. DMF (60 mg/kg) significantly decreased MDA levels and significantly increased GSH content compared with DEHP group in isolated kidney mitochondria. The mRNA expression levels of Nrf2 and HO-1 were significantly reduced in the DEHP group compared to the control group and were significantly increased in the DMF group compared to the DEHP group. p65NF-κB and TNFα mRNA expression levels were significantly increased in the DEHP group compared to the control group. However, DMF significantly decreased p65NF-κB and TNFα mRNA expression compared to the DEHP group. DMF can act as a nephroprotective agent against DEHP partly through modulation of oxidative stress, mitochondrial function, and inflammation. Graphical Abstract