MST3 Involvement in Na⁺ and K⁺ Homeostasis with Increasing Dietary Potassium Intake.

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 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 mice than that in wild-type (WT) mice. The MST3 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.

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