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

Wen Zheng^*,1, Johannes Kuhlicke^,1, Kristian Jäckel, Holger K. Eltzschig^,, Anurag Singh^*, Markus Sjöblom^*,2, Brigitte Riederer^*, Cornelia Weinhold^*, Ursula Seidler^*, Sean P. Colgan and Jörn Karhausen^,3

^* Abteilung Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany;

Universitätsklinik für Anästhesiologie und Intensivmedizin, Eberhard-Karls Universität Tübingen, Tübingen, Germany; and

Mucosal Inflammation Program, Division of Gastroenterology, University of Colorado, Health Sciences Center, Denver, Colorado, USA

³ Correspondence: Universitätsklinik für Anästhesiologie und Intensivmedizin, Eberhard-Karls Universität Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany. E-mail: joern.karhausen{at}medizin.uni-tuebingen.de

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 HCO₃^– 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.—Zheng, W., Kuhlicke, J., Jäckel, K., Eltzschig, H. K., Singh, A., Sjöblom, M., Riederer, B., Weinhold, C., Seidler, U., Colgan, S. P., Karhausen, J. Hypoxia inducible factor-1 (HIF-1) -mediated repression of cystic fibrosis transmembrane conductance regulator (CFTR) in the intestinal epithelium.

Key Words: anion transporter • ion movement • fluid secretion • mucosa