Abstract
Tubulointerstitial hypoxia plays a critical role in the pathogenesis of kidney injury, and hypoxia-inducible factor (HIF)-1 is a master regulator of cellular adaptation to hypoxia. Aside from oxygen molecules, factors that modify HIF-1 expression and functional operation remain obscure. Therefore, we sought to identify novel HIF-1-regulating genes in kidney. A short-hairpin RNA library consisting of 150 hypoxia-inducible genes was derived from a microarray analysis of the rat renal artery stenosis model screened for the effect on HIF-1 response. We report that CCAAT/enhancer-binding protein δ (CEBPD), a transcription factor and inflammatory response gene, is a novel HIF-1 regulator in kidney. CEBPD was induced in the nuclei of tubular epithelial cells in both acute and chronic hypoxic kidneys. In turn, CEBPD induction augmented HIF-1α expression and its transcriptional activity. Mechanistically, CEBPD directly bound to the HIF-1α promoter and enhanced its transcription. Notably, CEBPD was rapidly induced by inflammatory cytokines, such as IL-1β in a nuclear factor-κB-dependent manner, which not only increased HIF-1α expression during hypoxia, but was also indispensable for the non-hypoxic induction of HIF-1α. Thus our study provides novel insight into HIF-1 regulation in tubular epithelial cells and offers a potential hypoxia and inflammation link relevant in both acute and chronic kidney diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiopoietin-Like Protein 4
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Angiopoietins / genetics
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Angiopoietins / metabolism
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Animals
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CCAAT-Enhancer-Binding Protein-delta / genetics*
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CCAAT-Enhancer-Binding Protein-delta / metabolism
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Cell Hypoxia / genetics
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Cell Hypoxia / physiology
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Cells, Cultured
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Cisplatin / adverse effects
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Epithelial Cells / drug effects
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Gene Expression
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Gene Expression Regulation*
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Gene Knockdown Techniques
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Heme Oxygenase-1 / genetics
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Heme Oxygenase-1 / metabolism
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Humans
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Hypoxia / etiology
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Hypoxia / 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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Inflammation Mediators / pharmacology
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Kidney / pathology*
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Kidney Tubules, Proximal / cytology
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Kidney Tubules, Proximal / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Microarray Analysis
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NF-kappa B / metabolism
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Nephrectomy / adverse effects
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Nephritis / genetics
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Nephritis / metabolism*
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RNA, Messenger / metabolism
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RNA, Small Interfering
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Renal Artery Obstruction / complications
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Reperfusion Injury / complications
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Signal Transduction
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism
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Superoxide Dismutase-1
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Transcription, Genetic
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Up-Regulation
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Angiopoietin-Like Protein 4
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Angiopoietins
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Angptl4 protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Inflammation Mediators
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NF-kappa B
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RNA, Messenger
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RNA, Small Interfering
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SOD1 protein, human
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Vascular Endothelial Growth Factor A
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CCAAT-Enhancer-Binding Protein-delta
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Heme Oxygenase-1
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Sod1 protein, mouse
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Sod1 protein, rat
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Superoxide Dismutase
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Superoxide Dismutase-1
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Cisplatin