Estradiol suppresses mesangial cell type I collagen synthesis via activation of the MAP kinase cascade

Joel Neugarten, Ildiko Medve, Jun Lei, Sharon R. Silbiger

Research output: Contribution to journalArticle

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Abstract

We have previously shown that estradiol suppresses the synthesis of type I collagen by murine mesangial cells grown in the presence of serum via activation of the transcription factor activator protein-1 (AP-1). We hypothesized that estradiol upregulates AP-1 via activation of the mitogen-activated protein (MAP) kinase cascade, a signal transduction pathway that regulates AP-1 activity. Estradiol (10-10 to 10-7 M) upregulated the MAP kinase pathway in murine mesangial cells grown in the presence of serum in a dose-dependent manner. Activation was evident by 1 min, peaked at 10 min, and was completely dissipated by 2 h. In contrast, estradiol had no significant effect on total (phosphorylated + unphosphorylated) p44 extracellular signal-related protein kinase (ERK) or p42 ERK. Nuclear extracts isolated from mesangial cells treated with estradiol showed increased binding to a consensus sequence AP-1 binding oligonucleotide in gel shift assays. In contrast, nuclear extracts from cells exposed to PD-98059, a highly selective inhibitor of MAP kinase-ERK kinase 1 (MEK1) and MEK2, showed reduced binding. In addition, PD-98059 antagonizes the enhanced binding induced by estradiol. Estradiol (10-9 M) suppressed mesangial cell type I collagen synthesis (37.8 ± 2.4%, expressed as a percentage of control values, P < 0.001 vs. control). In contrast, PD-98059 increased type I collagen synthesis (344.6 ± 98.8, P < 0.01) and reversed the suppression of type I collagen synthesis induced by estradiol. The effects of estradiol, PD- 98059, and PD-98059 plus estradiol on type I collagen protein synthesis were closely paralleled by their effects on steady- state levels of mRNA for the α1 chain of type I collagen. These data suggest that estradiol suppresses type I collagen synthesis via upregulation of the MAP kinase cascade, leading to stimulation of AP-1 activity.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume277
Issue number6 46-6
StatePublished - Dec 1999

Fingerprint

Mesangial Cells
Collagen Type I
Mitogen-Activated Protein Kinases
Estradiol
Transcription Factor AP-1
Up-Regulation
MAP Kinase Kinase 1
Consensus Sequence
Cell Extracts
Serum
Protein Binding
Oligonucleotides
Protein Kinases
Signal Transduction
Transcription Factors
Gels
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Keywords

  • Gender
  • Glomerular mesangium
  • Matrix proteins
  • Mitogen-activated protein kinase
  • Sex hormones

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Estradiol suppresses mesangial cell type I collagen synthesis via activation of the MAP kinase cascade. / Neugarten, Joel; Medve, Ildiko; Lei, Jun; Silbiger, Sharon R.

In: American Journal of Physiology - Renal Physiology, Vol. 277, No. 6 46-6, 12.1999.

Research output: Contribution to journalArticle

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abstract = "We have previously shown that estradiol suppresses the synthesis of type I collagen by murine mesangial cells grown in the presence of serum via activation of the transcription factor activator protein-1 (AP-1). We hypothesized that estradiol upregulates AP-1 via activation of the mitogen-activated protein (MAP) kinase cascade, a signal transduction pathway that regulates AP-1 activity. Estradiol (10-10 to 10-7 M) upregulated the MAP kinase pathway in murine mesangial cells grown in the presence of serum in a dose-dependent manner. Activation was evident by 1 min, peaked at 10 min, and was completely dissipated by 2 h. In contrast, estradiol had no significant effect on total (phosphorylated + unphosphorylated) p44 extracellular signal-related protein kinase (ERK) or p42 ERK. Nuclear extracts isolated from mesangial cells treated with estradiol showed increased binding to a consensus sequence AP-1 binding oligonucleotide in gel shift assays. In contrast, nuclear extracts from cells exposed to PD-98059, a highly selective inhibitor of MAP kinase-ERK kinase 1 (MEK1) and MEK2, showed reduced binding. In addition, PD-98059 antagonizes the enhanced binding induced by estradiol. Estradiol (10-9 M) suppressed mesangial cell type I collagen synthesis (37.8 ± 2.4{\%}, expressed as a percentage of control values, P < 0.001 vs. control). In contrast, PD-98059 increased type I collagen synthesis (344.6 ± 98.8, P < 0.01) and reversed the suppression of type I collagen synthesis induced by estradiol. The effects of estradiol, PD- 98059, and PD-98059 plus estradiol on type I collagen protein synthesis were closely paralleled by their effects on steady- state levels of mRNA for the α1 chain of type I collagen. These data suggest that estradiol suppresses type I collagen synthesis via upregulation of the MAP kinase cascade, leading to stimulation of AP-1 activity.",
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