RRC ID 33213
Author Yamaguchi J, Tanaka T, Eto N, Nangaku M.
Title Inflammation and hypoxia linked to renal injury by CCAAT/enhancer-binding protein δ.
Journal Kidney Int
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.
Volume 88(2)
Pages 262-75
Published 2015-8-1
DOI 10.1038/ki.2015.21
PII S2157-1716(15)32181-X
PMID 25692954
PMC PMC4526770
MeSH Angiopoietin-Like Protein 4 Angiopoietins / genetics Angiopoietins / metabolism Animals CCAAT-Enhancer-Binding Protein-delta / genetics* CCAAT-Enhancer-Binding Protein-delta / metabolism Cell Hypoxia / genetics Cell Hypoxia / physiology Cells, Cultured Cisplatin / adverse effects Epithelial Cells / drug effects Gene Expression Gene Expression Regulation* Gene Knockdown Techniques Heme Oxygenase-1 / genetics Heme Oxygenase-1 / metabolism Humans Hypoxia / etiology Hypoxia / metabolism* Hypoxia-Inducible Factor 1, alpha Subunit / genetics* Hypoxia-Inducible Factor 1, alpha Subunit / metabolism Inflammation Mediators / pharmacology Kidney / pathology* Kidney Tubules, Proximal / cytology Kidney Tubules, Proximal / metabolism Male Mice Mice, Inbred C57BL Microarray Analysis NF-kappa B / metabolism Nephrectomy / adverse effects Nephritis / genetics Nephritis / metabolism* RNA, Messenger / metabolism RNA, Small Interfering Renal Artery Obstruction / complications Reperfusion Injury / complications Signal Transduction Superoxide Dismutase / genetics Superoxide Dismutase / metabolism Superoxide Dismutase-1 Transcription, Genetic Up-Regulation Vascular Endothelial Growth Factor A / genetics Vascular Endothelial Growth Factor A / metabolism
IF 8.945
Times Cited 35
DNA material pNF-kappaB RE-TK hRluc(F) (RDB05576)