title: MEK inhibitor, U0126, attenuates cisplatin-induced renal injury by decreasing inflammation and apoptosis.
abstract: BACKGROUND
  Although inflammation and apoptosis are known to play important roles in cisplatin nephrotoxicity, the exact intracellular signaling mechanisms are not well understood. Recent reports that extracellular signal-regulated kinase (ERK1/2) pathway mediates cisplatin-induced caspase activation and apoptosis in cultured renal tubular cells led us to investigate the effect of MAPK/ERK kinase (MEK) inhibitor, an immediate upstream of ERK1/2 in cisplatin-induced acute renal failure (ARF) in mice.
  
  
  METHODS
  The effect of MEK/ERK1/2 inhibition on kidney tumor necrosis factor-alpha (TNF-alpha (gene expression, inflammation, the activation of tissue caspases, and apoptosis were examined in addition to its effects on renal function and histology in cisplatin-induced ARF in mice.
  
  
  RESULTS
  Pretreatment of MEK inhibitor, U0126, decreased ERK1/2 phosphorylation following cisplatin administration with significant functional and histologic protection. This beneficial effect was accompanied by decrease in TNF-alpha gene expression level and inflammation, as well as in caspase 3 activity and apoptosis.
  
  
  CONCLUSIONS
  These data provide evidence that ERK1/2 pathway functions as an upstream signal for TNF-alpha-mediated inflammation and caspase 3-mediated apoptosis in cisplatin-induced ARF in mice and suggest that ERK1/2 can be a novel therapeutic target in cisplatin nephrotoxicity.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University, Seoul, Korea.
authors.forename: Sang-Kyung
authors.initials: SK
authors.lastname: Jo
authors.forename: Won Yong
authors.initials: WY
authors.lastname: Cho
authors.forename: Su Ah
authors.initials: SA
authors.lastname: Sung
authors.forename: Hyoung Kyu
authors.initials: HK
authors.lastname: Kim
authors.forename: Nam Hee
authors.initials: NH
authors.lastname: Won
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002070:Butadienes / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007249:Inflammation / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020169:Caspases; D002945:Cisplatin