title: Protective effect of peroxisome proliferator activator receptor (PPAR)-α and -γ ligands against methotrexate-induced nephrotoxicity.
abstract: BACKGROUND
  The anticancer drug methotrexate (MTX) may cause multi-organ toxicities, including nephrotoxicity.
  
  
  OBJECTIVE
  To investigate effects of peroxisome proliferator activator receptor (PPAR)-α and -γ agonists; fenofibrate (FEN) and pioglitazone (PIO), in MTX-induced nephrotoxicity in rats.
  
  
  METHODS
  Rats were given FEN or PIO (150 or 5 mg/kg/day, respectively) orally for 15 days. MTX was injected as a single dose of 20 mg/kg, i.p. at day 11 of experiment, with or without either PPAR agonists.
  
  
  RESULTS
  MTX induced renal toxicity, assessed by increase in serum urea and creatinine as well as histopathological alterations. MTX caused renal oxidative/nitrosative stress, indicated by decrease in GSH and catalase with increase in malondialdehyde and nitric oxide (NOx) levels. In addition, MTX increased renal level of the pro-inflammatory cytokine; tumor necrosis factor (TNF)-α and up-regulated the expression of both the inflammatory and apoptotic markers; NF-κB and caspase 3. Pre-administration of FEN or PIO to MTX-treated rats improved renal function and reversed oxidative/nitrosative parameters. Interestingly, pre-administration of PIO, but not FEN, decreased renal TNF-α level and NF-κB expression compared to MTX alone. Furthermore, PIO had more significant effect than FEN on reversing MTX-induced renal caspase 3 expression.
  
  
  CONCLUSIONS
  Both FEN and PIO conferred protection against MTX-induced nephrotoxicity through comparable amelioration of oxidative/nitrosative stress. FEN lacked any effect on TNF-α/NF-κB, which was reflected on its less improvement on renal histopathology and apoptosis.
  
  
  CONCLUSIONS
  At indicated dosage, PPAR-γ ligand; PIO shows better improvement of MTX-induced nephrotoxicity compared to PPAR-α ligand; FEN due to differential effect on TNF-α/NF-κB inflammatory pathway.
authors: Department of Pharmacology, Faculty of Medicine, Minia University , Minia , Egypt.
authors: Mohamed A
authors: MA
authors: Ibrahim
authors: Azza A K
authors: AA
authors: El-Sheikh
authors: Hanaa M
authors: HM
authors: Khalaf
authors: Aly M
authors: AM
authors: Abdelrahman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D003404:Creatinine / Q000097:blood / Q000652:urine; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008024:Ligands; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008727:Methotrexate / Q000009:adverse effects*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D008024:Ligands; D016328:NF-kappa B; D047493:PPAR alpha; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D008315:Malondialdehyde; D003404:Creatinine; D053148:Caspase 3; D008727:Methotrexate