Treatment With the Nrf2 Activator, Dimethyl Fumarate, Ameliorates Calcineurin Inhibitor Nephrotoxicity in Rats.

Abstract

Purpose: Cyclosporine A (CsA) is an immunosuppressive drug which is widely used to prevent rejection following organ transplantations. However, its therapeutic use is limited by nephrotoxicity which is in part mediated by oxidative stress. The present study aimed to investigate possible protective effects and mechanisms of action of the Nrf2 activator, Dimethyl Fumarate, (DMF) on CsA-induced nephrotoxicity. Methods: Male Sprague-Dawley rats were treated with CsA (n=8, 20 mg/kg/day i.p.), CsA + DMF (n=7, 50 mg/kg/day p.o.) for 28 days. Renal function, histopathology, and serum and tissue malondialdehyde (MDA) and tissue myeloperoxidase (MPO) levels and anti-oxidant enzyme expressions were evaluated. Results: DMF co-treatment ameliorated CsA-induced renal dysfunction as evidenced by significant decrease in serum creatinine (CsA 0.79 ± 0.02 mg/dl vs. CsA + DMF 0.62 ± 0.04 mg/dl, P=0.001) and urea (CsA 66.9 ± 0.4 mg/dl vs. CsA + DMF 53.3 ± 2.6 mg/dl, P<0.0001) levels, increase in urine creatinine and urea levels as well as improvement of creatinine clearance. DMF also significantly decreased serum and renal MDA and renal MPO content. The protein expression of NQO-1, a major cellular anti-oxidant and detoxifying enzyme was significantly enhanced by DMF administration in kidney. Conclusions: Administration of DMF has a protective potential against CsA nephrotoxicity. The protection afforded by CsA is mediated, at least in part, through inhibiting oxidative stress and inflammation and enhancing the antioxidant capacity.