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1 type IV
collagen gene transcription is mediated by TGF-
and inhibited by
estradiol
1 Nephrology Division, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10467; and 2 Penn Center for Molecular Studies of Kidney Diseases, Renal-Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania School of Medicine, Department of Medicine, Philadelphia, Pennsylvania 19104
We examined the hypothesis that fetal calf serum (FCS)
stimulates murine mesangial cell
1 type IV collagen
(COL4A1) gene transcription by increasing autocrine production of transforming growth
factor-
(TGF-) through a platelet-derived growth factor (PDGF)-dependent mechanism. PDGF-stimulated
COL4A1 gene transcription was
inhibited by neutralizing antibody to TGF- (119.3 ± 3.6 vs. 106.0 ± 6.2 relative luciferase units, expressed as a percentage of
control untreated cells, P < 0.003).
FCS-stimulated gene transcription was inhibited by neutralizing
antibody to PDGF (148.3 ± 4.1 vs. 136.7 ± 0.3 relative
luciferase units, P < 0.002) and by neutralizing antibody to TGF- (148.3 ± 4.1 vs.
127.1 ± 3.4 relative luciferase units,
P < 0.036). The inhibitory effect of
combined treatment with anti-PDGF and anti-TGF- antibody on gene
transcription was no greater than that of anti-TGF- antibody alone
[129.5 ± 0.53 vs. 127.1 ± 3.4 relative luciferase units,
P = not significant (NS)].
FCS-stimulated gene transcription was also inhibited by estradiol
(10
7 M) (148.4 ± 3.1 vs. 119.4 ± 8.1 relative luciferase units,
P < 0.019). In the presence of
estradiol, anti-TGF- antibody failed to further reduce
serum-stimulated gene transcription (119.4 ± 8.1 vs. 115.6 ± 9.8, P = NS), suggesting that
estradiol reverses FCS-stimulated
COL4A1 gene transcription by
antagonizing the actions of TGF-. Measurement of type IV collagen
synthesis by Western blotting confirmed that the intact gene responded
in a manner analogous to the promoter construct.
mesangial cells; sex hormones; estrogen; mesangial matrix; transforming growth factor-
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