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The regulation of Na+Cl− cotransporter by with-no-lysine kinase 4

Purpose of reviewAbundant evidence supports that the Na+Cl− cotransporter (NCC) activity is tightly regulated by the with-no-lysine (WNK) kinases. Here, we summarize the data regarding NCC regulation by WNKs, with a particular emphasis on WNK4. Recent findingsSeveral studies involving in-vivo and in-vitro models have provided paradoxical data regarding WNK4 regulation of the NCC. Although some studies show that WNK4 can activate the NCC, other equally compelling studies show that WNK4 inhibits the NCC. Recent studies have shown that WNK4 is regulated by the intracellular chloride concentration ([Cl−]i), which could account for these paradoxical results. In conditions of high [Cl−]i, WNK4 could act as an inhibitor via heterodimer formation with other WNKs. In contrast, when [Cl−]i is low, WNK4 can activate Ste20-related, proline–alanine-rich kinase (SPAK)/oxidative stress responsive kinase 1 (OSR1) and thus the NCC. Modulation of WNK4 by [Cl−]i has been shown to account for the potassium-sensing properties of the distal convoluted tubule. Other regulators of WNK4 include hormones and ubiquitination. SummaryModulation of WNK4 activity by [Cl−]i can account for its dual role on the NCC, and this has important physiological implications regarding the regulation of extracellular potassium concentration. Defective regulation of WNKs by ubiquitination explains most cases of familial hyperkalemic hypertension.