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Hypoxia‐inducible factor‐dependent production of profibrotic mediators by hypoxic Kupffer cells
Author(s) -
Copple Bryan Lloyd,
Moon JeonOK
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.117.4
Subject(s) - downregulation and upregulation , hypoxia inducible factors , kupffer cell , hepatic stellate cell , platelet derived growth factor , endocrinology , hypoxia (environmental) , growth factor , medicine , biology , platelet derived growth factor receptor , transcription factor , vascular endothelial growth factor , microbiology and biotechnology , cancer research , chemistry , immunology , receptor , biochemistry , organic chemistry , oxygen , gene , vegf receptors
Liver fibrosis develops when chronic liver injury stimulates cells in the liver to produce mediators that activate hepatic stellate cells and stimulate them to secrete collagen. Recent studies have shown that the hypoxia‐regulated transcription factor, hypoxia‐inducible factor‐1α (HIF‐1α), is essential for upregulation of profibrotic mediators, such as platelet‐derived growth factor (PDGF), in the liver during the development of liver fibrosis. What remains unknown, however, is the cell type‐specific regulation of profibrotic mediators by HIFs. Accordingly, in the present study the hypothesis was tested that HIFs regulate production of profibrotic mediators by hypoxic Kupffer cells. Exposure of Kupffer cells isolated from Control mice to 1% oxygen activated HIF‐1α, and increased mRNA levels of PDGF‐B, vascular endothelial cell growth factor, Angiopoietin‐1, and monocyte chemotactic protein‐1. Upregulation of all of these mediators by hypoxia was prevented in Kupffer cells isolated from hypoxia‐inducible factor‐1β‐Deficient mice. Results from these studies suggest that HIFs are critical regulators of profibrotic mediator production by hypoxic Kupffer cells. This study was supported by NIH grants DK073566 and RR021940.