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1 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
2 Research Institute of Molecular Biology, Vienna, Austria
3 Division of Biology, University of California, San Diego, La Jolla, CA 92093, USA
* To whom correspondence should be addressed. E-mail: vhaase{at}mail.med.upenn.edu.
CTGF plays a significant role in the development of renal fibrosis by mediating the fibrotic effects of TGF-
1 and has been shown to be hypoxia-inducible in human breast cancer cells. It has been suggested that hypoxia is an important underlying cause for the development of renal fibrosis through the modulation of pro-fibrotic genes. One of the key mediators of the cell's
response to lowered oxygen environments is hypoxia-inducible-factor-1 (HIF-1), a basic helixloop-helix transcription factor, which enables cells to adapt to hypoxia by regulating the expression of genes involved in increasing oxygen availability (VEGF, erythropoietin) and enhancing glucose uptake and metabolism (GLUT-1, PGK). In this paper we have used primary tubular epithelial cell cultures from a tetracycline inducible-Hif-1
knockout murine model to
further elucidate the role of Hif-1 in the hypoxic-induction of Ctgf expression. We show that
hypoxia response elements present upstream of Ctgf enable direct interaction of Hif-1 transcription factor with the Ctgf promoter resulting in increased transcription of Ctgf mRNA. Cells deficient for Hif-1 were incapable of inducing Ctgf mRNA in response to hypoxia suggesting an absolute requirement of Hif-1. Furthermore, the observed Hif-1 mediated hypoxicstimulation of Ctgf expression was found to occur independently of TGF-1 signaling. Our findings have important implications for a number of fibrotic disorders in which hypoxia, CTGF, and TGF-1 are involved including renal, dermal, hepatic and pulmonary fibrosis.
Keywords
CTGF,
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