Estradiol suppresses type I collagen synthesis in mesangial cells via activation of activator protein-1

Kidney Int. 1999 Apr;55(4):1268-76. doi: 10.1046/j.1523-1755.1999.00376.x.

Abstract

Background: Estradiol suppresses the synthesis of type I collagen by murine mesangial cells. However, neither the alpha 1(I) nor the alpha 2(I) collagen gene contains an estrogen-response element. Because estradiol modulates the transcription of several genes that lack an estrogen-response element but contain a regulatory activator protein-1 (AP-1) binding motif, we hypothesized that AP-1 may mediate estradiol-induced suppression of type I collagen synthesis.

Methods: We measured type I collagen synthesis in murine mesangial cells exposed to estradiol, phorbol 12-myristate 13-acetate (an activator of AP-1), or curcumin (an inhibitor of AP-1). We also assessed the effects of estradiol on the steady-state level of c-fos and c-jun mRNA and on the binding of mesangial cell nuclear extracts to an AP-1 consensus binding site oligonucleotide.

Results: Estradiol (10(-10) M to 10(-7) M) suppressed type I collagen synthesis by murine mesangial cells in a dose-dependent manner (10(-7) M, 43.7 +/- 8.2% of control values, P < 0.001). Phorbol 12-myristate 13-acetate (10 microM, four-hr exposure) also decreased type I collagen in the media. In contrast, curcumin (1 microM) increased type I collagen. Estradiol increased the steady-state level of c-fos mRNA twofold at 30 minutes, with a return to basal levels at one hour. This was associated with a greater than threefold increase in the binding of nuclear extracts from estradiol-treated mesangial cells to an AP-1 consensus binding site oligonucleotide. Estradiol-enhanced binding of nuclear extracts to the AP-1 oligonucleotide was reversed by cycloheximide.

Conclusions: These data suggest that estradiol suppresses collagen I synthesis by murine mesangial cells via enhanced AP-1 activity.

MeSH terms

  • Animals
  • Binding, Competitive / drug effects
  • Blotting, Northern
  • Blotting, Western
  • Cell Line, Transformed
  • Collagen / biosynthesis*
  • Cycloheximide / pharmacology
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology*
  • Estrogen Antagonists / pharmacology
  • Fulvestrant
  • Glomerular Mesangium / drug effects*
  • Glomerular Mesangium / metabolism*
  • Male
  • Mice
  • Mice, Inbred Strains
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-jun / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factor AP-1 / metabolism*

Substances

  • Estrogen Antagonists
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Transcription Factor AP-1
  • Fulvestrant
  • Estradiol
  • Collagen
  • Cycloheximide
  • Tetradecanoylphorbol Acetate