Am J Physiol Cell Physiol AJP: Regulatory, Integrative and Comparative Physiology
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Am J Physiol Cell Physiol (March 29, 2006). doi:10.1152/ajpcell.00564.2005
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Submitted on November 4, 2005
Accepted on March 19, 2006

Transcriptional Repression of Na-K-2Cl- Co-transporter (NKCC1) by Hypoxia Inducible Factor-1

Juan C Ibla1, Joseph Khoury1, Tianqing Kong2, Andreas Robinson2, and Sean P. Colgan2*

1 Center for Experimental Therapeutics, Brigham and Women's Hospital, Boston, Massachusetts, United States; Anesthesiology, Children's Hospital, Boston, Massachusetts, United States
2 Center for Experimental Therapeutics, Brigham and Women's Hospital, Boston, Massachusetts, United States

* To whom correspondence should be addressed. E-mail: colgan{at}zeus.bwh.harvard.edu.

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 hypoxia-inducible factor (HIF). Chromatin immunoprecipitation (ChIP) analysis identified a functional HIF binding site oriented on the antisense strand of genomic DNA downstream of the transcription start site (TSS) corresponding to the NKCC1 5' untranslated region (5'UTR). Additional in vivo studies using conditional Hif1{alpha}-null mice revealed that the loss of HIF-1{alpha} 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.




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