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JunD and HIF-1 mediate transcriptional activation of angiotensinogen by TGF-β1 in human lung fibroblasts

Department of Physiology, Michigan State University, East Lansing, Michigan, USA

¹Correspondence: Department of Physiology, Michigan State University, 3197 Biomedical and Physical Sciences Bldg., East Lansing, MI 48824, USA. E-mail: uhal{at}msu.edu

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.

Key Words: idiopathic pulmonary fibrosis • local angiotensin system • angiotensinogen promoter • activation protein-1