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

Chee-Hong Chan,Te-Ling Lu,Sheng-Nan Wu,Houng-Wei Li,Bo-Ying Bao

doi:10.3390/ijms22030999

Abstract

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.

Highlights

An increase in dietary K+ intake stimulates aldosterone release, which stimulates renal secretion, and does not influence Na+ retention
An increase in dietary K+ intake significantly increased both ENaC and ROMK currents; K+ loading-induced stimulation of Na+ and K+ currents was smaller in mice carrying pseudohypoaldosteronism type II (PHAII)-mimicking mutations [17]. These results indicate that molecules downstream of WNK4 may be involved in K+ loading-regulated ENaC and
Since we previously reported that MST3−/− mice have higher ENaC activity [18], we hypothesized that MST3−/− mice have higher ability to reabsorb Na+ with a low-Na

Summary

Introduction

An increase in dietary K+ intake stimulates aldosterone release, which stimulates renal secretion, and does not influence Na+ retention. Several Na+ and K+ channels coordinate to maintain K+ secretion without Na+ retention. The increased Na+ in the distal nephron stimulates K+. Secretion through ROMK due to an electrochemical gradient generated by reabsorption of. These channels are regulated by a group of serine/threonine kinases, WNKs. Mutations in WNK1 and WNK4 genes cause a hereditary disease known as pseudohypoaldosteronism type II (PHAII) characterized with hyperkalemic hypertension [5]. WNK4 is a physiological Cl− sensor that manipulates dietary K+ intake [6] and regulates NCC

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Conclusion