Hypoxia inducible factor-1 (HIF-1)-mediated repression of cystic fibrosis transmembrane conductance regulator (CFTR) in the intestinal epithelium

Abteilung Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover,.
The FASEB Journal (Impact Factor: 5.04). 10/2008; 23(1):204-13. DOI: 10.1096/fj.08-110221
Source: PubMed


Diarrhea is widespread in intestinal diseases involving ischemia and/or hypoxia. Since hypoxia alters stimulated Cl(-) and water flux, we investigated the influence of such a physiologically and pathophysiologically important signal on expression of the cystic fibrosis transmembrane conductance regulator (CFTR). Located on the apical membrane, this cAMP-activated Cl(-) channel determines salt and fluid transport across mucosal surfaces. Our studies revealed depression of CFTR mRNA, protein, and function in hypoxic epithelia. Chromatin immunoprecipitation identified a previously unappreciated binding site for the hypoxia inducible factor-1 (HIF-1), and promoter studies established its relevance by loss of repression following point mutation. Consequently, HIF-1 overexpressing cells exhibited significantly reduced transport capacity in colorimetric Cl(-) efflux studies, altered short circuit measurements, and changes in transepithelial fluid movement. Whole-body hypoxia in wild-type mice resulted in significantly reduced small intestinal fluid and HCO(3)(-) secretory responses to forskolin. Experiments performed in Cftr(-/-) and Nkcc1(-/-) mice underlined the role of altered CFTR expression for these functional changes, and work in conditional Hif1a mutant mice verified HIF-1-dependent CFTR regulation in vivo. In summary, our study clarifies CFTR regulation and introduces the concept of a HIF-1-orchestrated response designed to regulate ion and fluid movement across hypoxic intestinal epithelia.

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    • "The cystic fibrosis transmembrane conductance regulator protein (CFTR) has been postulated as an important regulator of pulmonary epithelial cell internalization of P. aeruginosa and the absence of a functional CFTR protein was associated with decreased P. aeruginosa internalization [36], [37]. Decreased expression of CFTR in response to hypoxia has been observed in intestinal epithelial cells [38]. To investigate whether decreased P. aeruginosa internalization in hypoxia is dependent upon a functional CFTR, we investigated bacterial uptake in the bronchoepithelial cell line 16HBE 14o- and CFBE41o- cells (homozygous for ΔF508 mutation of the CFTR gene). "
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    • "Two other clusters include regulatory proteins that control the activity of CFTR. HIF1A (HIF1A/ZNF197) negatively regulates CFTR [42] and protein kinase A (PRKACA/PKIA) positively regulates CFTR [23]. FCGR2A (FCGR2A/LGALS3) is a modulator as genetic variations have been associated with increased susceptibility to P. aeruginosa [43]. "
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