MEK inhibitor, U0126, attenuates cisplatin-induced renal injury by decreasing inflammation and apoptosis.
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.
Jo
Sang-Kyung
SK
Division of Nephrology, Department of Internal Medicine, Korea University, Seoul, Korea.
Cho
Won Yong
WY
Sung
Su Ah
SA
Kim
Hyoung Kyu
HK
Won
Nam Hee
NH
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
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