| Autor: |
Nakagawa, Takahiko, Li, Jin H., Garcia, Gabriela, Mu, Wei, Piek, Ester, Böttinger, Erwin P., Chen, Yan, Zhu, Hong J., Kang, Duk-Hee, Schreiner, George F., Lan, Hui Y., Johnson, Richard J. |
| Rok vydání: |
2004 |
| Předmět: |
|
| Zdroj: |
Kidney International. 66(2):605-613 |
| ISSN: |
0085-2538 |
| DOI: |
10.1111/j.1523-1755.2004.00780.x |
| Popis: |
TGF-β induces proangiogenic and antiangiogenic factors via parallel but distinct Smad pathways.BackgroundAngiogenesis 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-β1 (TGF-β1), but the mechanism remains unclear.MethodsWe examined the role of TGF-β1 and its signaling pathways in mediating expression of these two molecules. Rat proximal tubular cells (NRK52E) were stimulated with TGF-β1 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-β1 was also examined. In addition, the effect of conditioned media from NRK52E and Smad knockout cells was examined on endothelial cell proliferation.ResultsInduction of VEGF-A and TSP-1 by TGF-β1 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-β1. Conditioned media from NRK52E, which was stimulated by TGF-β1 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.ConclusionR-Smads have distinct roles in mediating theexpression of pro- and antiangiogenic growth factors in response to TGF-β1. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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