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TGF-beta induces proangiogenic and antiangiogenic factors via parallel but distinct Smad pathways

Title
TGF-beta induces proangiogenic and antiangiogenic factors via parallel but distinct Smad pathways
Authors
Nakagawa, TLi, JHGarcia, GMu, WPiek, EBottinger, EPChen, YZhu, HJKang, DHSchreiner, GFLan, HYJohnson, RJ
Ewha Authors
강덕희
SCOPUS Author ID
강덕희scopus
Issue Date
2004
Journal Title
KIDNEY INTERNATIONAL
ISSN
0085-2538JCR Link
Citation
vol. 66, no. 2, pp. 605 - 613
Keywords
VEGFTSP-1sFlt-1Smad KO cellendothelial cell proliferation
Publisher
BLACKWELL PUBLISHING INC
Indexed
SCI; SCIE; SCOPUS WOS
Abstract
Background. Angiogenesis has a key role in numerous disease processes. One of the most important angiogenic factors is vascular endothelial growth factor (VEGF-A), whereas thrombospondin-1 (TSP-1) is a major antiangiogenic factor. Recent studies have shown that VEGF-A as well as TSP-1 is regulated by transforming growth factor-beta1 (TGF-beta1), but the mechanism remains unclear. Methods. We examined the role of TGF-beta1 and its signaling pathways in mediating expression of these two molecules. Rat proximal tubular cells (NRK52E) were stimulated with TGF-beta1 to induce VEGF-A and TSP-1 synthesis. To clarify roles of receptor-activated Smads (R-Smads), we blocked Smad signaling using overexpression of the inhibitory Smad, Smad7, and by using fibroblasts from wild-type or knockout mice. To confirm the antiantigenic role of Smads, soluble Flt-1 regulation in response to TGF-beta1 was also examined. In addition, the effect of conditioned media from NRK52E and Smad knockout cells was examined on endothelial cell proliferation. Results. Induction of VEGF-A and TSP-1 by TGF-beta1 in NRK52E cells was associated with activation of pathway-restricted R-Smads (Smad2 and 3) and blocking these Smads by overexpression of Smad7 blocked their induction. By using of Smad knockout cells, Smad3 was shown to have a key role in the stimulation of VEGF-A expression whereas Smad2 was critical for TSP-1 expression. Consistent with the hypothesis that Smad2 has an antiangiogenic function, we also demonstrated that Smad2, but not Smad3, mediated the expression of VEGF-A antagonist, soluble VEGF-A receptor sFlt-1, in response to TGF-beta1. Conditioned media from NRK52E, which was stimulated by TGF-beta1 for 24 hours, did not induce endothelial cell proliferation. However, conditioned media from Smad2 knockout induced endothelial cell proliferation, whereas endothelial cell proliferation was inhibited by Smad3 knockout-derived conditioned media. Conclusion. R-Smads have distinct roles in mediating the expression of pro- and antiangiogenic growth factors in response to TGF-beta1.
DOI
10.1111/j.1523-1755.2004.00780.x
Appears in Collections:
의과대학 > 의학과 > Journal papers
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