Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2006) 11 P397

University of Edinburgh, Edinburgh, United Kingdom.


WNK1 (With-No-K, lysine) and WNK4 are serine/threonine kinases, mutated in Gordon syndrome (Pseudohypoaldosteronism Type II), a dominant, hypertensive, hyperkalaemic disorder; implicating this novel WNK pathway in normal regulation of blood pressure (BP) and electrolyte balance. Previous Xenopus oocyte work implicates WNK4 in regulation of K+ secretion via ROMK (renal outer medullary K+ channel) and Cl- transport pathways both paracellularly via tight junctions (claudins), and transcellularly via the thiazide-sensitive NaCl cotransporter (NCCT) and NKCC1. WNK1 may in turn inhibit WNK4.

To begin to clarify the role of this pathway we detail renal WNK pathway gene expression in mice, a species closely mirroring these aspects of human physiology. We have identified an important, short, kinase-deficient WNK1 isoform (WNK1-S) is overwhelmingly predominant in kidney. Expression of WNK1-S and WNK4 is strongest in distal tubule dropping sharply in collecting duct and with WNK4 also expressed in thick ascending limb (TAL, including macula densa), extending the spectrum of potential WNK4 targets. Interestingly, the WNK4-NKCC1 interaction is reportedly dependent on SPAK, a kinase which also interacts with NKCC2 (predominantly expressed in TAL).

In vivo this novel WNK pathway responds to chronic changes in dietary potassium and aldosterone, particularly upregulation of WNK1-S and WNK4 with high potassium which via inhibition of NCCT and enhanced distal sodium delivery would facilitate enhanced K+-excretion. As potassium intake drops the WNK pathway modulation of sodium reabsorption in distal tubule coordinates with H+/K+-ATPase and striking reciprocal ROMK isoform-specific expression changes.

These in vivo findings have important implications for our understanding of the WNK pathway and the regulation of BP, K+ and acid-base balance.

Volume 11

8th European Congress of Endocrinology incorporating the British Endocrine Societies

European Society of Endocrinology 
British Endocrine Societies 

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