Hypoxia inducible factor-1 (HIF-1)-mediated repression of cystic fibrosis transmembrane conductance regulator (CFTR) in the intestinal epithelium.
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.
Zheng
Wen
W
Abteilung Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover,.
Kuhlicke
Johannes
J
Jäckel
Kristian
K
Eltzschig
Holger K
HK
Singh
Anurag
A
Sjöblom
Markus
M
Riederer
Brigitte
B
Weinhold
Cornelia
C
Seidler
Ursula
U
Colgan
Sean P
SP
Karhausen
Jörn
J
D000818:Animals; D001483:Base Sequence; D001692:Biological Transport / Q000502:physiology*; D045744:Cell Line, Tumor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D010101:Oxygen Consumption / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2
C578877:SLC12A2 protein, human; C578878:Slc12a2 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D010100:Oxygen
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