Endocrine Abstracts

WNK1 and WNK4 are serine/threonine kinases, With-No-K (lysine) residue at a key catalytic position within the active site. Mutations in either cause Pseudohypoaldosteronism type II (Gordon syndrome), an autosomal dominant, hypertensive, hyperkalaemic disorder, especially responsive to thiazide diuretics (first line treatment for essential hypertension). This novel WNK pathway is implicated in normal regulation of blood pressure (BP) and distal nephron Na⁺/K⁺ balance. Heterozygote WNK1 knockout mice have low BP (homozygotes: embryonic lethal). Xenopus oocyte work implicates WNK4 as inhibiting thiazide sensitive cotransporter (TSC) Na⁺ reabsorption and K⁺ secretion (via ROMK). WNK1 may in turn inhibit WNK4. To better understand this key WNK pathway, we have isolated mouse WNK1 and WNK4 cDNA sequences, identified an important, short, kinase-deficient kidney-predominant WNK1 isoform, and here we report the mRNA distribution, splicing and physiological regulation of this WNK pathway in adult mouse. WNK4 is expressed strongly in adult kidney, moderately in testis, intestine, pituitary and in some other tissues at lower level. Renal WNK4 expression extends from medullary collecting duct (MCD, key for K⁺ balance) proximally to important Na+ reabsorption sites including early distal convoluted tubule (DCT) - site of TSC expression where co-localisation with short, kinase-deficient WNK1 occurs. Moreover, prominent tissue-specific splicing causes important coding region alterations in corresponding predicted WNK proteins. Following chronic alteration in dietary electrolyte intake or aldosterone treatment there are significant changes in WNK pathway expression. These novel findings enhance our understanding of the pathways regulating BP and electrolyte balance in distal nephron.