Inflammation and hypoxia linked to renal injury by CCAAT/enhancer-binding protein δ

Kidney Int. 2015 Aug;88(2):262-75. doi: 10.1038/ki.2015.21. Epub 2015 Feb 18.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Angiopoietin-Like Protein 4
  • Angiopoietins
  • Angptl4 protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Inflammation Mediators
  • NF-kappa B
  • RNA, Messenger
  • RNA, Small Interfering
  • SOD1 protein, human
  • Vascular Endothelial Growth Factor A
  • CCAAT-Enhancer-Binding Protein-delta
  • Heme Oxygenase-1
  • Sod1 protein, mouse
  • Sod1 protein, rat
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Cisplatin