Familial Hyperkalemic Hypertension (FHHt, also known as Type II Pseudohypoaldosteronism or Gordon's syndrome) is a disorder of elevated blood pressure and potassium levels, and is phenotypically the """"""""mirror image"""""""" of Gitelman's syndrome. FHHt is caused by mutations in the serine-threonine kinases WNK1 and WNK4, proteins highly expressed in the renal distal convoluted tubule (DCT). The sponsor has shown previously that WNK1 and WNK4 interact to regulate the thiazide-sensitive NaCI cotransporter (NCC). This proposal focuses on WNK1, whose transcription is upregulated in patients with FHHt due to a deletion within intron 1 of the WNK1 gene. WNK1 undergoes tissue-specific splicing, and the predominant renal isoform (kWNK1), contains a fractured kinase domain which is probably defective. Preliminary data suggest that kWNK1 may exert a dominant-negative effect on NCC cotransport by inhibiting the regulatory effect of WNK1. The experiments proposed herein serve to clarify the functional role of WNK1 and kWNK1 in the DCT. To this end, we will study the functional effects of kWNK1 on NCC cotransport in a Xenopus oocyte expression system. We will test for kWNK1 interactions with WNK1 with immunoprecipitation studies and in vitro kinase assays. We also propose a series of experiments that serve to identify cis elements within the first intron of the WNK1 gene that may be ablated in FHHt, leading to the upregulation of full length WNK1 relative to kWNK1.
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| Rozansky, David J; Cornwall, Tonya; Subramanya, Arohan R et al. (2009) Aldosterone mediates activation of the thiazide-sensitive Na-Cl cotransporter through an SGK1 and WNK4 signaling pathway. J Clin Invest 119:2601-12 |
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| Subramanya, Arohan R; Yang, Chao-Ling; Zhu, Xiaoman et al. (2006) Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform. Am J Physiol Renal Physiol 290:F619-24 |
