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

Abstract

Diarrhea is widespread in intestinal diseases involving ischemia and/or hypoxia. Since hypoxia alters stimulated C P and water flux, we investigated the influence of such a physiologically and pathophysiologi‐cally important signal on expression of the cystic fibrosis transmembrane conductance regulator (CFTR). Located on the apical membrane, this cAMP‐activated C P channel determines salt and fluid transport across mucosal surfaces. Our studies revealed depression of CFTR mRNA, protein, and function in hypoxic epithe‐lia. Chromatin immunoprecipitation identified a previ‐ously unappreciated binding site for the hypoxia induc‐ible 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 C P efflux studies, altered short circuit measurements, and changes in transepithelial fluid movement. Whole‐body hypoxia in wild‐type mice re‐sulted 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 Hifla 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., Kuh‐licke, 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 epithe‐lium. FASEB J. 23, 204‐213 (2009)