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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/L790    most recent 00099.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Martin, M. M. Articles by Elton, T. S. Search for Related Content PubMed PubMed Citation Articles by Martin, M. M. Articles by Elton, T. S.

TGF-1 stimulates human AT₁ receptor expression in lung fibroblasts by cross talk between the Smad, p38 MAPK, JNK, and PI3K signaling pathways

Divisions of ¹Pharmacology and ²Pharmaceutics, College of Pharmacy, ³Division of Cardiology, Department of Medicine, and ⁴Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio

Submitted 14 March 2007 ; accepted in final form 26 June 2007

Both angiotensin II (ANG II) and transforming growth factor-1 (TGF-1) are thought to be involved in mediating pulmonary fibrosis. Interactions between the renin-angiotensin system (RAS) and TGF-1 have been well documented, with most studies describing the effect of ANG II on TGF-1 expression. However, recent gene expression profiling experiments demonstrated that the angiotensin II type 1 receptor (AT₁R) gene was a novel TGF-1 target in human adult lung fibroblasts. In this report, we show that TGF-1 augments human AT₁R (hAT₁R) 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-1 transcriptionally activates the hAT₁R gene and does not influence hAT₁R mRNA stability. Pharmacological inhibitors and specific siRNA knockdown experiments demonstrate that the TGF-1 type 1 receptor (TRI/ALK5), Smad2/3, and Smad4 are essential for TGF-1-stimulated hAT₁R 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-1-stimulated increase in hAT₁R 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 hAT₁R following TGF-1 treatment in hPFB. This study supports the hypothesis that a self-potentiating loop exists between the RAS and the TGF-1 signaling pathways and suggests that ANG II and TGF-1 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.

G protein-coupled receptors; pulmonary fibrosis; angiotensin II; transforming growth factor-1; mitogen-activated protein kinase; c-Jun NH₂-terminal kinase; phosphatidylinositol 3-kinase