Nephrology Dialysis Transplantation, Vol 13, Issue 3 573-579, Copyright © 1998 by Oxford University Press
R Bertelli, F Valenti, R Oleggini, G Caridi, P Altieri, D Coviello, G Botti, R Ravazzolo and G Ghiggeri
Background: TGF-{beta}1 modulates the cellular
expression of extracellular matrix (ECM) in several renal cell systems
in vitro and is considered a determinant of ECM
accumulation in tubulointerstitial fibrosis. Methods:
We evaluated the effects of TGF-{beta}1 on collagen transcription,
expression, and removal of the relevant collagens by rat tubuloepithelial
cells (NRK 52E) and both rat and monkey interstitial fibroblasts (NRK 49F,
CV1) in vitro. Results:
TGF-{beta}1 upregulated the expression of &agr;1 (III) collagen by
fibroblasts (+300%) without affecting its removal. In parallel, a threefold
increment of COL3A1 mRNA was found. Experiments of cell transfection
employing CV1 fibroblasts as the unique suitable model, and chimaeric
constructs of COL3A1 and COL5A2 promoters fused to the luciferase reporter
gene, demonstrated a twofold stimulation of a large 1436 COL3A1 promoter
construct and negligible effects on shorter fragments, suggesting the
presence of a positive response element in a region of COL3A1 promoter
between -1375 and -579. TGF-{beta}1 did not influence COL5A2 mRNA and
the relative promoter activity in renal fibroblasts. With NRK 52E cell
line, TGF-{beta}1 induced comparable increment of both &agr;1(III)
collagen expression (+300%) and COL3A1 mRNA (+300%) without affecting the
COL3A1 promoter activity of any constructs. TGF-{beta}1 upregulated the
expression of &agr;2(V) collagen chain (+500%) and COL5A2 mRNA (+500%)
with a stimulatory effect (+100%) on a 1177 bp fragment of COL5A2 promoter.
In this case a relevant inhibitory effect of TGF-{beta}1 on removal of
&agr;2(V) by supernatants of NRK 52E was also observed, indicating a
double regulatory role of the cytokine on both transcription and removal of
this component of ECM. Conclusion: Taken together
these data indicate that TGF-{beta}1 is a potent stimulator of
&agr;1(III) collagen expression by renal fibroblast cell lines
in vitro, the basic mechanism being stimulation of
COL3A1 transcription. With renal epithelial cell lines, TGF-{beta}1
mainly upregulated the expression of type V collagen with the most relevant
effect on stimulation of collagen transcription and inhibition of its
removal. Tubular epithelial cells and renal fibroblasts should play
distinct roles in renal fibrosis induced by TGF-{beta}1 in
vivo. Key words: TGF-{beta}1; collagen;
extracellular matrix; interstitial fibrosis
ORIGINAL ARTICLES
Cell-specific regulation of &agr;1(III) and &agr;2(V) collagen by TGF-{beta}1 in tubulointerstitial cell models
Nephrology Section, G Gaslini Institute Largo Gaslini 5, I-16148 Genova, Italy; Institute of Biology and Genetics (IBIG), University of Genova, Genova, Italy; Corresponding author
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