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K⁺ loading inhibits NKCC2 (Na-K-Cl cotransporter) and NCC (Na-Cl cotransporter) in the early distal tubules, resulting in Na⁺ delivery to the late distal convoluted tubules (DCTs). In the DCTs, Na⁺ entry through ENaC (epithelial Na channel) drives K⁺ secretion through ROMK (renal outer medullary potassium channel). WNK4 (with-no-lysine 4) regulates the NCC/NKCC2 through SAPK (Ste20-related proline-alanine-rich kinase)/OSR1 (oxidative stress responsive). K⁺ loading increases intracellular Cl⁻, which binds to the WNK4, thereby inhibiting autophosphorylation and downstream signals. Acute K⁺ loading-deactivated NCC was not observed in Cl⁻-insensitive WNK4 mice, indicating that WNK4 was involved in K⁺ loading-inhibited NCC activity. However, chronic K⁺ loading deactivated NCC in Cl⁻-insensitive WNK4 mice, indicating that other mechanisms may be involved. We previously reported that mammalian Ste20-like protein kinase 3 (MST3/STK24) was expressed mainly in the medullary TAL (thick ascending tubule) and at lower levels in the DCTs. MST3<i>^−/−</i> mice exhibited higher ENaC activity, causing hypernatremia and hypertension. To investigate MST3 function in maintaining Na⁺/K⁺ homeostasis in kidneys, mice were fed diets containing various concentrations of Na⁺ and K⁺. The 2% KCl diets induced less MST3 expression in MST3<i>^−/−</i> mice than that in wild-type (WT) mice. The MST3<i>^−/−</i> mice had higher WNK4, NKCC2-S130 phosphorylation, and ENaC expression, resulting in lower urinary Na⁺ and K⁺ excretion than those of WT mice. Lower urinary Na⁺ excretion was associated with elevated plasma [Na⁺] and hypertension. These results suggest that MST3 maintains Na⁺/K⁺ homeostasis in response to K⁺ loading by regulation of WNK4 expression and NKCC2 and ENaC activity.