Sodium Chloride Cotransporter Regulation by WNK Kinase

Johns Hopkins University, Baltimore MD

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): WNKs (with no lysine (K)) are a newly described novel subfamily of serine/threonine kinases implicated in controlling the ionic permeability of epithelia. Mutations in WNK1 and WNK4 kinases are found to cause pseudohypoaldosteronism type II (PHA II), also referred to as Gordon syndrome. PHA II is a rare autosomal dominant disorder featuring hypertension, hyperkalemia and metabolic acidosis. Its clinical features are reversed by a thiazide diuretic, a sodium chloride cotransporter (NCC) inhibitor. Immunofluorescent studies and Northern blot analysis demonstrated that both WNK1 and WNK4 are present in a variety of polarized epithelia involved in chloride ion transport, such as kidney, clonic crypts, sweat ducts, pancreatic ducts, biliary ducts, epididymis and the ependyma of the brain. Mutations in WNK kinases resulting in PHA II suggest that WNK kinase is involved in the regulation of sodium chloride handling by the distal nephron. Recent studies have shown an inhibitory effect of WNK4 on NCC activity and surface expression of NCC in Xenopus oocytes, further demonstrating that WNK4 kinase regulates NCC function through direct or indirect mechanisms. This research proposal is to examine the role of WNK4 kinase in NCC regulation in the renal tubular cells. The hypothesis to be tested is that inappropriate targeting and/or function of the WNK4 kinase will affect NCC regulation directly by altering the NCC processing and/or indirectly by altering the phosphorylation of NCC in mammalian cells. This hypothesis is supported by strong preliminary data that surface expression of NCC is significantly reduced by WNK4. In contrast, NCC surface expression is unaffected by WNK4 mutants in African green monkey kidney (Cos-7) cells. Further investigating the regulation of NCC by WNK4 will provide important information to understanding the physiological role of WNK4 kinase and help to identify the underlying mechanisms of PHA II that are crucial in better understanding the pathogenesis of essential hypertension.