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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Transcriptional repression of Na-K-2Cl cotransporter NKCC1 by hypoxia-inducible factor-1

¹Department of Anesthesia Perioperative and Pain Medicine, Children’s Hospital, and ²Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

Submitted 4 November 2005 ; accepted in final form 19 March 2006

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 Cl^– secretion after epithelial hypoxia. A screen of known ion transporters in Cl^–-secreting epithelia revealed selective downregulation of Na-K-2Cl cotransporter NKCC1 mRNA, protein, and function. Subsequent studies identified transcriptional repression of NKCC1 mediated by hypoxia-inducible factor (HIF). Chromatin immunoprecipitation analysis identified a functional HIF binding site oriented on the antisense strand of genomic DNA downstream of the transcription start site corresponding to the NKCC1 5'-untranslated region. Additional in vivo studies using conditional Hif1a-null mice revealed that the loss of HIF-1 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.

transcription; ion transport; chloride secretion; epithelia

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