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HIF‐dependent Repression of Na‐K‐2Cl‐ Co‐transporter (NKCC1) in Hypoxia
Author(s) -
Colgan Sean P.,
Khoury Joseph,
Robinson Andreas,
Kong Tianqing,
Ibla Juan C.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1094-c
Subject(s) - psychological repression , hypoxia (environmental) , chromatin immunoprecipitation , microbiology and biotechnology , transcription factor , biology , hypoxia inducible factors , chemistry , biochemistry , gene expression , gene , oxygen , promoter , organic chemistry
Tissue edema is commonly associated with hypoxia. Generally, such episodes of fluid accumulation are self‐limiting. At present, little is known about mechanisms to compensate excessive fluid transport. Here, we describe an adaptive mechanism to dampen fluid loss during hypoxia. Initial studies confirmed previous observations of attenuated electrogenic chloride secretion following epithelial hypoxia. A screen of known ion transporters in Cl‐ secreting epithelia revealed selective down‐regulation of the Na‐K‐2Cl‐cotransporter (NKCC1) mRNA, protein and function. Subsequent studies identified transcriptional repression of NKCC1 mediated by the transcription factor hypoxia‐inducible factor (HIF). Chromatin immunoprecipitation (ChIP) and mutagenesis analysis identified a functional HIF binding site oriented on the antisense strand of the NKCC1 5′ untranslated region (5′UTR). Additional in vivo studies using conditional Hif1a‐null mice revealed that the loss of HIF‐1a in Cl‐ secreting epithelia results in a loss of NKCC1 repression. These studies describe a novel regulatory pathway for NKCC1 transcriptional repression by hypoxia. These results suggest that HIF‐dependent repression of epithelial NKCC1 may provide a compensatory mechanism to prevent excessive fluid loss during hypoxia.