WNK kinases: molecular regulators of integrated epithelial ion transport

The WNK kinases are a recently discovered family of serine-threonine kinases that have been shown to play an essential role in the regulation of electrolyte homeostasis. This review focuses on the recent evidence elucidating the functions of these kinases in normal and disease physiology.

Mutations in WNK1 and WNK4 have been shown to cause pseudohypoaldosteronism type II, a disease featuring hypertension with hyperkalemia. Recent work has demonstrated that WNK4 is a potent inhibitor of diverse epithelial transporters including the thiazide-sensitive sodium chloride co-transporter (NCCT) and the renal outer medullary potassium ion channel. In addition, WNK4 activity promotes paracellular chloride ion flux. Importantly, mutations in WNK4 that cause disease have divergent effects on these transport pathways. WNK4 mutations relieve the inhibition of NCCT, increase the inhibition of the renal outer medullary potassium ion channel, and further increase paracellular chloride ion flux. These findings can explain the observed physiological abnormalities in patients with pseudohypoaldosteronism type II, and support a model in which WNK4 is a molecular switch that can alter the balance between chloride ion reabsorption and potassium ion secretion. The WNK kinases are also found in diverse epithelia throughout the body that are involved in chloride ion flux, suggesting that these kinases may play a general role in the regulation of chloride ion flux.

The WNK kinases define a previously unrecognized signaling pathway that is essential for the integrated regulation of electrolyte homeostasis. Their function has implications for understanding the coordinated regulation of electrolyte homeostasis and blood pressure, and identifies WNKs as dynamic regulators of the paracellular flux pathway.