title: Treatment With Dimethyl Fumarate Attenuates Calcineurin Inhibitor-induced Nephrotoxicity.
abstract: BACKGROUND
  Cyclosporine A (CsA) is an immunosuppressive drug which has been widely used to prevent rejection after organ transplantation. However, its therapeutic use is limited by nephrotoxicity, in part mediated by oxidative stress. The present study aims to investigate the protective effects of dimethyl fumarate (DMF) on CsA-induced nephrotoxicity by enhancing the antioxidant defense system.
  
  
  METHODS
  Male Sprague-Dawley rats were treated with CsA (n = 8, 20 mg/kg per day intraperitoneally) or CsA + DMF (n = 7, 50 mg/kg per day orally) for 28 days. Renal function, histopathology, malondialdehyde (MDA), myeloperoxidase levels, and antioxidant enzyme expression were determined.
  
  
  RESULTS
  The DMF cotreatment 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, as well as improvement of creatinine clearance. Dimethyl fumarate also significantly decreased serum MDA and renal tissue MDA and myeloperoxidase contents. The protein expression of NAD(P)H quinone oxidoreductase-1, a major cellular antioxidant 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 DMF is mediated in part through inhibiting oxidative stress and inflammation and enhancing the antioxidant capacity.
authors.affiliation: 1 Department of Surgery, University of California, Irvine, CA. 2 Department of Medicine, University of California, Irvine, CA.
authors.forename: Chie
authors.initials: C
authors.lastname: Takasu
authors.forename: Nosratola D
authors.initials: ND
authors.lastname: Vaziri
authors.forename: Shiri
authors.initials: S
authors.lastname: Li
authors.forename: Lourdes
authors.initials: L
authors.lastname: Robles
authors.forename: Kelly
authors.initials: K
authors.lastname: Vo
authors.forename: Mizuki
authors.initials: M
authors.lastname: Takasu
authors.forename: Christine
authors.initials: C
authors.lastname: Pham
authors.forename: Shuman
authors.initials: S
authors.lastname: Liu
authors.forename: Seyed H
authors.initials: SH
authors.lastname: Farzaneh
authors.forename: Clarence E
authors.initials: CE
authors.lastname: Foster
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Stamos
authors.forename: Hirohito
authors.initials: H
authors.lastname: Ichii
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D065095:Calcineurin Inhibitors / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000633:toxicity; D000069462:Dimethyl Fumarate; D005650:Fumarates / Q000494:pharmacology*; D006084:Graft Rejection / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000633:toxicity; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051265:NF-E2-Related Factor 1 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D016377:Organ Transplantation / Q000009:adverse effects; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000975:Antioxidants; D065095:Calcineurin Inhibitors; D005650:Fumarates; D007166:Immunosuppressive Agents; D051265:NF-E2-Related Factor 1; C495632:Nfe2l1 protein, rat; D009569:Nitric Oxide; D008315:Malondialdehyde; D016572:Cyclosporine; D003404:Creatinine; D009195:Peroxidase; D000069462:Dimethyl Fumarate