Increasing plasma [K+] by intravenous potassium infusion reduces NCC phosphorylation and drives kaliuresis and natriuresis

Am J Physiol Renal Physiol. 2014 May 1;306(9):F1059-68. doi: 10.1152/ajprenal.00015.2014. Epub 2014 Mar 5.


Dietary potassium loading results in rapid kaliuresis, natriuresis, and diuresis associated with reduced phosphorylation (p) of the distal tubule Na(+)-Cl(-) cotransporter (NCC). Decreased NCC-p inhibits NCC-mediated Na(+) reabsorption and shifts Na(+) downstream for reabsorption by epithelial Na(+) channels (ENaC), which can drive K(+) secretion. Whether the signal is initiated by ingesting potassium or a rise in plasma K(+) concentration ([K(+)]) is not understood. We tested the hypothesis, in male rats, that an increase in plasma [K(+)] is sufficient to reduce NCC-p and drive kaliuresis. After an overnight fast, a single 3-h 2% potassium (2%K) containing meal increased plasma [K(+)] from 4.0 ± 0.1 to 5.2 ± 0.2 mM; increased urinary K(+), Na(+), and volume excretion; decreased NCC-p by 60%; and marginally reduced cortical Na(+)-K(+)-2Cl(-) cotransporter (NKCC) phosphorylation 25% (P = 0.055). When plasma [K(+)] was increased by tail vein infusion of KCl to 5.5 ± 0.1 mM over 3 h, significant kaliuresis and natriuresis ensued, NCC-p decreased by 60%, and STE20/SPS1-related proline alanine-rich kinase (SPAK) phosphorylation was marginally reduced 35% (P = 0.052). The following were unchanged at 3 h by either the potassium-rich meal or KCl infusion: Na(+)/H(+) exchanger 3 (NHE3), NHE3-p, NKCC, ENaC subunits, and renal outer medullary K(+) channel. In summary, raising plasma [K(+)] by intravenous infusion to a level equivalent to that observed after a single potassium-rich meal triggers renal kaliuretic and natriuretic responses, independent of K(+) ingestion, likely driven by decreased NCC-p and activity sufficient to shift sodium reabsorption downstream to where Na(+) reabsorption and flow drive K(+) secretion.

Keywords: feedback; hyperkalemia; potassium homeostasis; sodium transport regulation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Disease Models, Animal
  • Epithelial Sodium Channels / metabolism
  • Hyperkalemia / blood*
  • Hyperkalemia / chemically induced
  • Hyperkalemia / physiopathology
  • Hyperkalemia / urine
  • Infusions, Intravenous
  • Kidney / metabolism*
  • Kidney / physiopathology
  • Male
  • Natriuresis*
  • Phosphorylation
  • Potassium / administration & dosage
  • Potassium / blood*
  • Potassium / urine
  • Potassium Channels / metabolism
  • Potassium, Dietary / blood
  • Potassium, Dietary / urine
  • Protein-Serine-Threonine Kinases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sodium / blood
  • Sodium / urine*
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers / metabolism
  • Solute Carrier Family 12, Member 3 / metabolism
  • Time Factors


  • Epithelial Sodium Channels
  • Potassium Channels
  • Potassium, Dietary
  • Slc12a3 protein, rat
  • Slc9a3 protein, rat
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers
  • Solute Carrier Family 12, Member 3
  • Sodium
  • PAS domain kinases
  • Protein-Serine-Threonine Kinases
  • Potassium