Calcineurin inhibitors block sodium-chloride cotransporter dephosphorylation in response to high potassium intake

Kidney Int. 2017 Feb;91(2):402-411. doi: 10.1016/j.kint.2016.09.001. Epub 2016 Oct 27.


Dietary potassium intake is inversely related to blood pressure and mortality. Moreover, the sodium-chloride cotransporter (NCC) plays an important role in blood pressure regulation and urinary potassium excretion in response to potassium intake. Previously, it was shown that NCC is activated by the WNK4-SPAK cascade and dephosphorylated by protein phosphatase. However, the mechanism of NCC regulation with acute potassium intake is still unclear. To identify the molecular mechanism of NCC regulation in response to potassium intake, we used adult C57BL/6 mice fed a 1.7% potassium solution by oral gavage. We confirmed that acute potassium load rapidly dephosphorylated NCC, which was not dependent on the accompanying anions. Mice were treated with tacrolimus (calcineurin inhibitor) and W7 (calmodulin inhibitor) before the oral potassium loads. Dephosphorylation of NCC induced by potassium was significantly inhibited by both tacrolimus and W7 treatment. There was no significant difference in WNK4, OSR1, and SPAK expression after high potassium intake, even after tacrolimus and W7 treatment. Another phosphatase, protein phosphatase 1, and its endogenous inhibitor I-1 did not show a significant change after potassium intake. Hyperkaliuria, induced by high potassium intake, was significantly suppressed by tacrolimus treatment. Thus, calcineurin is activated by an acute potassium load, which rapidly dephosphorylates NCC, leading to increased urinary potassium excretion.

Keywords: calcineurin; phosphatase; potassium; sodium-chloride cotransporter.

MeSH terms

  • Animals
  • Calcineurin / metabolism*
  • Calcineurin Inhibitors / pharmacology*
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Hydrogen-Ion Concentration
  • Kidney / drug effects*
  • Kidney / metabolism
  • Male
  • Mice, Inbred C57BL
  • Phosphorylation
  • Potassium, Dietary / blood
  • Potassium, Dietary / metabolism*
  • Potassium, Dietary / urine
  • Protein Kinase Inhibitors / pharmacology
  • Protein Phosphatase 1 / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Renal Elimination / drug effects*
  • Signal Transduction / drug effects
  • Solute Carrier Family 12, Member 3 / drug effects
  • Solute Carrier Family 12, Member 3 / metabolism
  • Sulfonamides / pharmacology
  • Tacrolimus / pharmacology*
  • Time Factors
  • Transcription Factors / metabolism


  • Calcineurin Inhibitors
  • Potassium, Dietary
  • Protein Kinase Inhibitors
  • Slc12a3 protein, mouse
  • Solute Carrier Family 12, Member 3
  • Sulfonamides
  • Transcription Factors
  • W 7
  • Prkwnk4 protein, mouse
  • Stk39 protein, mouse
  • OXSR1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Calcineurin
  • Protein Phosphatase 1
  • Tacrolimus