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TGF-ß1 stimulates human AT^sub 1^ receptor expression in lung fibroblasts by cross talk between the Smad, p38 MAPK, JNK, and PI3K signaling pathways

Both angiotensin II (ANG II) and transforming growth factor-β1 (TGF-β1) are thought to be involved in mediating pulmonary fibrosis. Interactions between the renin-angiotensin system (RAS) and TGF-β1 have been well documented, with most studies describing the effect of ANG II on TGF-β1 expression. Ho...

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Published in:American journal of physiology. Lung cellular and molecular physiology 2007-09, Vol.293 (3), p.L790
Main Authors: Martin, Mickey M, Buckenberger, Jessica A, Jiang, Jinmai, Malana, Geraldine E
Format: Article
Language:English
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Summary:Both angiotensin II (ANG II) and transforming growth factor-β1 (TGF-β1) are thought to be involved in mediating pulmonary fibrosis. Interactions between the renin-angiotensin system (RAS) and TGF-β1 have been well documented, with most studies describing the effect of ANG II on TGF-β1 expression. However, recent gene expression profiling experiments demonstrated that the angiotensin II type 1 receptor (...) gene was a novel TGF-β1 target in human adult lung fibroblasts. In this report, we show that TGF-β1 augments human ... (...) steady-state mRNA and protein levels in a dose- and time-dependent manner in primary human fetal pulmonary fibroblasts (hPFBs). Nuclear run-on experiments demonstrate that TGF-β1 transcriptionally activates the ... gene and does not influence ... mRNA stability. Pharmacological inhibitors and specific siRNA knockdown experiments demonstrate that the TGF-β1 type 1 receptor (TRI/ALK5), Smad2/3, and Smad4 are essential for TGF-β1-stimulated ... expression. Additional pharmacological inhibitor and small interference RNA experiments also demonstrated that p38 MAPK, JNK, and phosphatidylinositol 3-kinase (PI3K) signaling pathways are also involved in the TGF-β1-stimulated increase in ... density. Together, our results suggest an important role for cross talk among Smad, p38 MAPK, JNK, and PI3K pathways in mediating the augmented expression of ... following TGF-β1 treatment in hPFB. This study supports the hypothesis that a self-potentiating loop exists between the RAS and the TGF-β1 signaling pathways and suggests that ANG II and TGF-β1 may cooperate in the pathogenesis of pulmonary fibrosis. The synergy between these systems may require that both pathways be simultaneously inhibited to treat fibrotic lung disease. (ProQuest: ... denotes formulae/symbols omitted.)
ISSN:1040-0605
1522-1504