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Title: WNK kinases : novel regulators of electrolyte balance and blood pressure
Author: O'Reilly, Michelle
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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The association of mutations in WNK1 and WNK4 with Gordon syndrome was a major breakthrough also implicating these novel serine/threonine kinases in the regulation of electrolyte balance and blood pressure (BP). Thus, elucidation of the novel pathway in which these WNK kinases participate should lead to fundamental advances in our understanding of these phenomena. In situ hybridization and PCR studies revealed tissue-specific splicing for WNK1 and widespread and intricate regulation of WNK1 and WNK4 expression during development involving both epithelial and non-epithelial tissues. The importance of this expression is highlighted by the WNK1-/- mouse which is embryonic lethal by mid-gestation. Kidney has by far the strongest expression of WNK4 of any major organ. Moreover, whilst WNK1 is widely expressed, the kidney has an additional kidney-specific smaller WNK1 transcript. Detailed studies of the nature and expression of these WNK gene transcripts were undertaken. These showed that rather than merely being a polyA-tail variant the short kidney-specific WNK1 transcript (WNK1-S) actually differed from the longer widely distributed transcript (WNK1-L) in a much more functionally significant way. It lacked the first four coding exons yielding a predicted protein lacking the kinase domain. The WNK pathway at least in kidney may involve features beyond a simple kinase cascade. WNK1-S and WNK4 are highly expressed in distal convoluted tubule (DCT) and connecting tubule (CNT), adjacent distal nephron segments known to play key roles in electrolyte balance and BP control. Additional novel domains of substantial WNK4 expression were found in thick ascending limb (TAL; including macula densa), while WNK1-L was uniformly expressed at low-level throughout kidney. These findings indicate that the spectrum of WNK interacting partners may be determined by their local renal distributions, a factor which is frequently overlooked at present. Work then extended to investigating how the WNK pathway, and genes likely linked to it, respond to dynamic changes in renal K+, Na+ and CI- load and aldosterone level. This work has revealed key dietary electrolyte and aldosterone driven transcriptional regulation of elements of the WNK pathway and the renal outer medullary K+ channel (ROMK), leading to better understanding of how this pathway may participate in the in vivo regulation of electrolyte balance and BP. In vivo findings, in conjunction with clues from reported in vitro functional studies, allow the development of a model of how the WNK pathway may function in an integrated way which fits well with normal renal electrolyte handling and also how this is altered in treatment with thiazide diuretics or when mutated in Gordon syndrome.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available