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Hypoxia is a pro-fibrogenic stimulus for human renal tubular epithelial cells

Orphanides, Chrystalla; (1999) Hypoxia is a pro-fibrogenic stimulus for human renal tubular epithelial cells. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Progressive renal diseases of diverse etiology are characterised by tubulo-interstitial fibrosis which ultimately leads to renal failure. One important feature of TIF is thickening of the tubular basement membrane with altered matrix composition. The underlying mechanisms which mediate the qualitative and quantitative changes in the TBM have not been identified; however one initiating stimulus may be hypoxia arising from microvascular injury. Since hypoxia is a potent regulator of gene expression it was hypothesised that oxygen deprivation may provide a stimulus for changes in ECM metabolism in PTE. The effects of hypoxia on PTE matrix synthesis and degradation were examined using an in vitro model. In human PTE, hypoxia (1%02, 24hrs) increased total collagen production, decreased MMP-2 actvity and increased Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) protein. Collagen IV mRNA levels decreased while collagen [alpha]1(1) mRNA increased, suggesting induction of an atypical, interstitial collagen. Hypoxia-induced changes persisted on re-oxygenation, with increased expression of TIMP mRNAs. Neutralising antibody studies demonstrated that these effects were not due to the induction of the major pro-fibrogenic cytokine TGF-[beta]1. Moreover, the hypoxia-induced increase in collagen [alpha]1(1) was not mediated by a secreted, soluble factor, suggesting a direct effect of hypoxia on the collagen [alpha]1(1) gene. Transient-transfection experiments demonstrated that collagen [alpha]1(1) promoter activity is stimulated by hypoxia and that this effect is independent of HIF-1, the transcription factor which regulates transcription in many hypoxia-responsive genes. This suggests an alternative mechanism for regulation of the collagen [alpha]1(1) promoter by hypoxia. In summary, this thesis demonstrates that hypoxia is a pro-fibrogenic stimulus for PTE in vitro simultaneously increasing matrix production and decreasing turnover. Similar effects of hypoxia in vivo would lead to the qualitative and quantitative changes observed in TIF.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Hypoxia is a pro-fibrogenic stimulus for human renal tubular epithelial cells
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Renal disease
URI: https://discovery.ucl.ac.uk/id/eprint/10105014
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