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- Title
Hypoxia promotes fibrogenesis in human renal fibroblasts.
- Authors
Norman, Jill T.; Clark, Ian M.; Garcia, Patricia L.; Norman, J T; Clark, I M; Garcia, P L
- Abstract
<bold>Background: </bold>The mechanisms underlying progressive renal fibrosis are unknown, but the common association of fibrosis and microvascular loss suggests that hypoxia per se may be a fibrogenic stimulus. <bold>Methods: </bold>To determine whether human renal fibroblasts (HRFs), the primary matrix-producing cells in the tubulointerstitium, possess oxygen-sensitive responses relevant to fibrogenesis, cells were exposed to 1% O2 in vitro. <bold>Results: </bold>Hypoxia simultaneously stimulated extracellular matrix synthesis and suppressed turnover with increased production of collagen alpha1(I) (Coll-I), decreased expression of collagenase, and increased tissue inhibitor of metalloproteinase (TIMP)-1. These effects are time dependent, require new RNA and protein synthesis, and are specific to hypoxia. The changes in Coll-I and TIMP-1 gene expression involve a heme-protein O2 sensor and protein kinase- and tyrosine kinase-mediated signaling. Although hypoxia induced transforming growth factor-beta1 (TGF-beta1), neutralizing anti-TGF-beta1-antibody did not block hypoxia-induced Coll-I and TIMP-1 mRNA expression. Furthermore, hypoxic-cell conditioned-medium had no effect on the expression of these mRNAs in naive fibroblasts, suggesting direct effects on gene transcription. Transient transfections identified a hypoxia response element (HRE) in the TIMP-1 promoter and demonstrated HIF-1-dependent promoter activation by decreased ambient pO2. <bold>Conclusions: </bold>These data suggest that hypoxia co-ordinately up-regulates matrix production and decreases turnover in renal fibroblasts. The results support a role for hypoxia in the pathogenesis of fibrosis and provide evidence for novel, direct hypoxic effects on the expression of genes involved in fibrogenesis.
- Subjects
HYPOXEMIA; FIBROBLASTS; MICROCIRCULATION disorders; KIDNEY diseases; PROTEIN metabolism; RNA physiology; RNA analysis; CELL culture; CELL division; CELL physiology; CHRONIC kidney failure; COBALT; COLLAGEN; COMPARATIVE studies; CULTURE media (Biology); DEFEROXAMINE; EXTRACELLULAR space; GENES; GENETIC techniques; GROWTH factors; KIDNEYS; RESEARCH methodology; MEDICAL cooperation; MUSCLE proteins; OXYGEN; PREVENTIVE health services; PROTEIN-tyrosine kinases; PROTEINS; PROTEOLYTIC enzymes; RESEARCH; TRANSFERASES; EVALUATION research; CELL size; CHELATING agents; CHEMICAL inhibitors; PHARMACODYNAMICS; METABOLISM
- Publication
Kidney International, 2000, Vol 58, Issue 6, p2351
- ISSN
0085-2538
- Publication type
journal article
- DOI
10.1046/j.1523-1755.2000.00419.x