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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  −/−   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.

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