MEK inhibitor, U0126, attenuates cisplatin-induced renal injury by decreasing inflammation and apoptosis

Sang Kyung Jo, Won Yong Cho, Su Ah Sung, Hyoung Kyu Kim, Nam Hee Won

Research output: Contribution to journalArticle

166 Citations (Scopus)

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-α (TNF-α(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-α gene expression level and inflammation, as well as in caspase 3 activity and apoptosis. Conclusion. These data provide evidence that ERK1/2 pathway functions as an upstream signal for TNF-α-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.

Original languageEnglish
Pages (from-to)458-466
Number of pages9
JournalKidney International
Volume67
Issue number2
DOIs
Publication statusPublished - 2005 Jan 1

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Mitogen-Activated Protein Kinase Kinases
Cisplatin
Apoptosis
Inflammation
Kidney
Wounds and Injuries
Acute Kidney Injury
MAP Kinase Signaling System
Caspases
Caspase 3
MAP Kinase Kinase 2
Gene Expression
Mitogen-Activated Protein Kinase 1
U 0126
Histology
Tumor Necrosis Factor-alpha
Phosphorylation

Keywords

  • Apoptosis
  • Caspase
  • Cisplatin
  • ERK
  • Inflammation
  • TNF-α

ASJC Scopus subject areas

  • Nephrology

Cite this

MEK inhibitor, U0126, attenuates cisplatin-induced renal injury by decreasing inflammation and apoptosis. / Jo, Sang Kyung; Cho, Won Yong; Sung, Su Ah; Kim, Hyoung Kyu; Won, Nam Hee.

In: Kidney International, Vol. 67, No. 2, 01.01.2005, p. 458-466.

Research output: Contribution to journalArticle

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