TGF-β1 activates MAP kinase in human mesangial cells: A possible role in collagen expression

Tomoko Hayashida*, Anne Christine Poncelet, Susan C. Hubchak, H. William Schnaper

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

178 Scopus citations

Abstract

Background. Although the pathogenic relevance of transforming growth factor-β (TGF-β) to glomerular sclerosis has been established, the intracellular mechanisms by which TGF-β induces extracellular matrix accumulation are not fully understood. We examined whether the mitogen- activated protein (MAP) kinase pathway is involved in TGF-β1-induced collagen expression by cultured human mesangial cells. Methods. The activation of MAP kinase pathways by TGF-β1 was assessed by immunoblot with anti-phospho-ERK or -JNK antibodies and by transfection of plasmids expressing pathway-specific transcription activators fused to the DNA-binding domain of GAL4, as well as a GAL4 response element-luciferase reporter gene. The role of MAP kinase was assessed using biochemical inhibitors and transiently expressed dominant negative mutant constructs. The effects on TGF-β1-induced α1 (I) collagen expression were evaluated by Northern blot and by activation of a transiently transfected α1 (I) promoter-luciferase reporter construct. Results. ERK and JNK phosphorylation occurred 30 minutes and one hour, respectively, after TGF-β1 treatment. A biochemical blockade of the ERK pathway inhibited TGF-β1-induced α1(I) collagen expression. A dominant negative mutant of ERK1 but not of JNK decreased α1(I) gene promoter activation. Activation of the TGF-β-responsive p3TP-Lux construct was partially inhibited by cotransfection of an ERK1 dominant negative mutant. Conclusion. These data indicate that MAP kinase pathways can be activated by TGF-β1 in mesangial cells and that the ERK MAP kinase plays a role in TGF-β-stimulated collagen I expression. Because we have shown previously that SMADs mediate TGF-β1-stimulated collagen I expression, our findings raise the possibility of interactions between the MAP kinase and the SMAD pathways.

Original languageEnglish (US)
Pages (from-to)1710-1720
Number of pages11
JournalKidney international
Volume56
Issue number5
DOIs
StatePublished - 1999

Keywords

  • Cytokine
  • Mitogen activated protein kinase
  • Sclerosing process
  • Transforming growth factor-β
  • Type I collagen

ASJC Scopus subject areas

  • Nephrology

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