Abstract
To examine whether hypoxia-inducible factor (HIF)-1α mediates the profibrotic effects of angiotensin II, we treated cultured renal medullary interstitial cells with angiotensin II and found that it increased HIF-1α levels. This was accompanied by a significant upregulation of collagen I/III, the tissue inhibitor of metalloproteinase-1, elevation of the proliferation marker proliferating cell nuclear antigen, and a transdifferentiation marker vimentin. All these effects of angiotensin II were completely blocked by siRNA for HIF-1α but not HIF-2α. Overexpression of a prolyl-hydroxylase domain-containing protein 2 (PHD2) transgene, the predominant renal HIF prolyl-hydroxylase, attenuated the effects of angiotensin II and its gene silencing enhanced the effects of angiotensin II. Removal of hydrogen peroxide eliminated angiotensin II-induced profibrotic effects. A 2-week infusion of rats with angiotensin II increased the expression of HIF-1α and α-smooth muscle actin, another marker of transdifferentiation, in renal medullary interstitial cells in vivo. Thus, our study suggests that HIF-1α mediates angiotensin II-induced profibrotic effects through activation of cell transdifferentiation. We propose that redox regulation of prolyl-PHD2 plays a critical role in angiotensin II-induced activation of HIF-1α in renal cells.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Actins / metabolism
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Angiotensin II / administration & dosage
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Angiotensin II / metabolism*
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Transdifferentiation
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Cells, Cultured
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Collagen Type I / metabolism
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Collagen Type III / metabolism
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Fibrosis
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Hydrogen Peroxide / metabolism
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Hypoxia-Inducible Factor-Proline Dioxygenases
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Kidney Medulla / metabolism*
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Kidney Medulla / pathology
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Male
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Procollagen-Proline Dioxygenase / genetics
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Procollagen-Proline Dioxygenase / metabolism
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Proliferating Cell Nuclear Antigen / metabolism
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RNA Interference
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Rats
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Rats, Sprague-Dawley
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Tissue Inhibitor of Metalloproteinase-1 / metabolism
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Transfection
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Up-Regulation
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Vimentin / metabolism
Substances
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Actins
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Basic Helix-Loop-Helix Transcription Factors
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Collagen Type I
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Collagen Type III
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Hif1a protein, rat
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Hypoxia-Inducible Factor 1, alpha Subunit
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Proliferating Cell Nuclear Antigen
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Tissue Inhibitor of Metalloproteinase-1
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Vimentin
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smooth muscle actin, rat
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Angiotensin II
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endothelial PAS domain-containing protein 1
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Hydrogen Peroxide
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Procollagen-Proline Dioxygenase
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Egln1 protein, rat
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Hypoxia-Inducible Factor-Proline Dioxygenases