By Icon Health Publications
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Additional info for Aldosterone - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References
Willerson Chair; Internal Medicine; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 01-APR-1994; Project End 31-JUL-2005 Summary: The H+ -K+ -ATPase alpha2 (HKalpha2) gene expressed in kidney and colon plays a critical role in the maintenance of body potassium and acid-base balance during chronic hypokalemia and chronic sodium depletion. The broad objectives of the proposed research are to identify the molecular mechanisms underlying the transcriptional regulation of this gene in the kidney and colon during these commonly encountered clinical conditions.
The selective effects of mineralocorticoids and glucocorticoids on HKalpha2 transcription in the distal colon and kidney will be analyzed to determine whether transcriptional induction is specific to the cognate nuclear receptors for these ligands. DNase I hypersensitivity assays and in vivo footprinting coupled with analysis of HKalpha2 regulatory regionreporter gene constructs will be used to map, at single nucleotide resolution, cellspecific promoter and enhancer elements in epithelial cell lines derived from the renal medullary collecting duct and distal colon under normal conditions and in response to low external K+ and aldosterone.
Previous work found that Nedd4 and Nedd4-2 reduce ENaC surface expression by targeting the channel for degradation. A defect in this pathway is responsible for Liddle's syndrome. Conversely, serum and glucocorticoidregulated kinase (SGK), a down-stream mediator of aldosterone, increases ENaC surface expression. Our preliminary studies suggest the novel hypothesis that these two pathways are not independent, but that they converge in a common pathway to regulate Na+ absorption. The goal of this project is to test the hypothesis that SGK modulates ENaC surface expression in part through Nedd4-2 binding and phosphorylation, and to understand the mechanisms involved.