K+-induced natriuresis is preserved during Na+ depletion and accompanied by inhibition of the Na+-Cl- cotransporter

Am J Physiol Renal Physiol. 2013 Oct 15;305(8):F1177-88. doi: 10.1152/ajprenal.00201.2013. Epub 2013 Aug 28.


During hypovolemia and hyperkalemia, the kidneys defend homeostasis by Na(+) retention and K(+) secretion, respectively. Aldosterone mediates both effects, but it is unclear how the same hormone can evoke such different responses. To address this, we mimicked hypovolemia and hyperkalemia in four groups of rats with a control diet, low-Na(+) diet, high-K(+) diet, or combined diet. The low-Na(+) and combined diets increased plasma and kidney ANG II. The low-Na(+) and high-K(+) diets increased plasma aldosterone to a similar degree (3-fold), whereas the combined diet increased aldosterone to a greater extent (10-fold). Despite similar Na(+) intake and higher aldosterone, the high-K(+) and combined diets caused a greater natriuresis than the control and low-Na(+) diets, respectively (P < 0.001 for both). This K(+)-induced natriuresis was accompanied by a decreased abundance but not phosphorylation of the Na(+)-Cl(-) cotransporter (NCC). In contrast, the epithelial Na(+) channel (ENaC) increased in parallel with aldosterone, showing the highest expression with the combined diet. The high-K(+) and combined diets also increased WNK4 but decreased Nedd4-2 in the kidney. Total and phosphorylated Ste-20-related kinase were also increased but were retained in the cytoplasm of distal convoluted tubule cells. In summary, high dietary K(+) overrides the effects of ANG II and aldosterone on NCC to deliver sufficient Na(+) to ENaC for K(+) secretion. K(+) may inhibit NCC through WNK4 and help activate ENaC through Nedd4-2.

Keywords: SPAK; WNK4; aldosterone; angiotensin II; epithelial Na+ channel; hyperkalemia; hypovolemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldosterone / blood
  • Aldosterone / physiology
  • Angiotensin II / physiology
  • Animals
  • Hyperkalemia / metabolism*
  • Male
  • Natriuresis / physiology*
  • Potassium, Dietary / administration & dosage*
  • Rats
  • Rats, Sprague-Dawley
  • Renin-Angiotensin System / physiology
  • Sodium Chloride Symporters / metabolism*
  • Sodium Chloride, Dietary / antagonists & inhibitors*
  • Sodium Chloride, Dietary / metabolism


  • Potassium, Dietary
  • Sodium Chloride Symporters
  • Sodium Chloride, Dietary
  • Angiotensin II
  • Aldosterone