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TGF-beta induces proangiogenic and antiangiogenic factors via parallel but distinct Smad pathways
- TGF-beta induces proangiogenic and antiangiogenic factors via parallel but distinct Smad pathways
- Nakagawa, T; Li, JH; Garcia, G; Mu, W; Piek, E; Bottinger, EP; Chen, Y; Zhu, HJ; Kang, DH; Schreiner, GF; Lan, HY; Johnson, RJ
- Ewha Authors
- SCOPUS Author ID
- Issue Date
- Journal Title
- KIDNEY INTERNATIONAL
- vol. 66, no. 2, pp. 605 - 613
- VEGF; TSP-1; sFlt-1; Smad KO cell; endothelial cell proliferation
- BLACKWELL PUBLISHING INC
- SCI; SCIE; SCOPUS
- 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.
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