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Journals The FASEB Journal June 2009

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JunD and HIF-1{alpha} mediate transcriptional activation of angiotensinogen by TGF-{beta}1 in human lung fibroblasts

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Earlier work showed that TGF-β1 potently increases angiotensinogen (AGT) gene mRNA in primary human lung fibroblasts. Here the mechanism of TGF-β1-induced AGT expression was studied in the IMR90 human lung fibroblast cell line. The increase in AGT mRNA induced by TGF-β1 was completely blocked by actinomycin-D. TGF-β1 increased the activity of a full-length human AGT promoter-luciferase reporter (AGT-LUC) but did not alter AGT mRNA half-life. Serial deletion analyses revealed that 67% of TGF-β-inducible AGT-LUC activity resides in a small domain of the AGT core promoter; this domain contains binding sites for hypoxia-inducible factor (HIF)-1 and activation protein-1 (AP-1) transcription factors. TGF-β1 increased HIF-1 protein abundance and the activity of a hypoxia-responsive element reporter; overexpression of HIF-1 increased basal AGT-LUC activity. Both oligonucleotide pulldown and chromatin immunoprecipitation assays revealed increased binding of JunD and HIF-1 to the AGT core promoter in response to TGF-β1. TGF-β1-inducible AGT-LUC was reduced by an AP-1 dominant negative or by mutation of the AP-1 site. Knockdown of either JunD or HIF-1 individually by siRNA partially reduced AGT-LUC. In contrast, simultaneous knockdown of both JunD and HIF-1 completely eliminated TGF-β1-inducible AGT-LUC activity. These data suggest that TGF-β1 up-regulates AGT transcription in human lung fibroblasts through a mechanism that requires both JunD and HIF-1 binding to the AGT core promoter. They also suggest a molecular mechanism linking hypoxia signaling and fibrogenic stimuli in the lungs.—Abdul-Hafez, A., Shu, R., Uhal, B. D. JunD and HIF-1 mediate transcriptional activation of angiotensinogen by TGF-β1 in human lung fibroblasts.

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Article Details
Abdul-Hafez, Amal; Shu, Ruijie; Uhal, Bruce D.
The FASEB Journal , Volume 23 (6): 1655
Fed of American Socs for Experimental Biology – Jun 1, 2009
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