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

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 ? (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-1? expression and its transcriptional activity. Mechanistically, CEBPD directly bound to the HIF-1? promoter and enhanced its transcription. Notably, CEBPD was rapidly induced by inflammatory cytokines, such as IL-1? in a nuclear factor-?B-dependent manner, which not only increased HIF-1? expression during hypoxia, but was also indispensable for the non-hypoxic induction of HIF-1?. 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.

SUBMITTER: Yamaguchi J 

PROVIDER: S-EPMC4526770 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature