title: Inflammation and hypoxia linked to renal injury by CCAAT/enhancer-binding protein δ.
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.
authors.affiliation: Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Junna
authors.initials: J
authors.lastname: Yamaguchi
authors.affiliation: Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Kyowa Hakko Kirin, Tokyo, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Eto
authors.affiliation: Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002945:Cisplatin / Q000009:adverse effects; D004847:Epithelial Cells / Q000187:drug effects; D015870:Gene Expression; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000209:etiology / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D018836:Inflammation Mediators / Q000494:pharmacology; D007668:Kidney / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D016328:NF-kappa B / Q000378:metabolism; D009392:Nephrectomy / Q000009:adverse effects; D009393:Nephritis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D012078:Renal Artery Obstruction / Q000150:complications; D015427:Reperfusion Injury / Q000150:complications; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014158:Transcription, Genetic; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C000606290:SOD1 protein, human; D042461:Vascular Endothelial Growth Factor A; D051743:CCAAT-Enhancer-Binding Protein-delta; D051547:Heme Oxygenase-1; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D002945:Cisplatin