Mst3 involvement in na+ and k+ homeostasis with increasing dietary potassium intake

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

Research output: Contribution to journalArticlepeer-review

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 autophosphoryla-tion 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 ac-tivity. 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 hyper-natremia 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+ ho-meostasis in response to K+ loading by regulation of WNK4 expression and NKCC2 and ENaC activity.

Original languageEnglish
Article number999
Pages (from-to)1-15
Number of pages15
JournalInternational journal of molecular sciences
Volume22
Issue number3
DOIs
Publication statusPublished - 2021 Feb 1

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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