Dietary anions control potassium excretion: it is more than a poorly absorbable anion effect

Lama Al-Qusairi, Mohammed Z. Ferdaus, Truyen D. Pham, Dimin Li, P. Richard Grimm, Ava M. Zapf, Delaney C. Abood, Ebrahim Tahaei, Eric Delpire, Susan M. Wall, Paul A. Welling

Research output: Contribution to journalArticlepeer-review


The urinary potassium (K þ ) excretion machinery is upregulated with increasing dietary K þ , but the role of accompanying dietary anions remains inadequately characterized. Poorly absorbable anions, including HCO-3 , are thought to increase K þ secretion through a transepithelial voltage effect. Here, we tested if they also influence the K þ secretion machinery. Wild-type mice, aldosterone synthase (AS) knockout (KO) mice, or pendrin KO mice were randomized to control, high-KCl, or high-KHCO3 diets. The K þ secretory capacity was assessed in balance experiments. Protein abundance, modification, and localization of K þ -secretory transporters were evaluated by Western blot analysis and confocal microscopy. Feeding the high-KHCO3 diet increased urinary K þ excretion and the transtubular K þ gradient significantly more than the high-KCl diet, coincident with more pronounced upregulation of epithelial Na þ channels (ENaC) and renal outer medullary K þ (ROMK) channels and apical localization in the distal nephron. Experiments in AS KO mice revealed that the enhanced effects of HCO-3 were aldosterone independent. The high-KHCO3 diet also uniquely increased the large-conductance Ca2 þ -activated K þ (BK) channel b4-subunit, stabilizing BKa on the apical membrane, the Cl-/HCO-3 exchanger, pendrin, and the apical KCl cotransporter (KCC3a), all of which are expressed specifically in pendrin-positive intercalated cells. Experiments in pendrin KO mice revealed that pendrin was required to increase K þ excretion with the high-KHCO3 diet. In summary, HCO-3 stimulates K þ excretion beyond a poorly absorbable anion effect, upregulating ENaC and ROMK in principal cells and BK, pendrin, and KCC3a in pendrin-positive intercalated cells. The adaptive mechanism prevents hyperkalemia and alkalosis with the consumption of alkaline ash-rich diets but may drive K þ wasting and hypokalemia in alkalosis. NEW & NOTEWORTHY Dietary anions profoundly impact K þ homeostasis. Here, we found that a K þ -rich diet, containing HCO-3 as the counteranion, enhances the electrogenic K þ excretory machinery, epithelial Na þ channels, and renal outer medullary K þ channels, much more than a high-KCl diet. It also uniquely induces KCC3a and pendrin, in B-intercalated cells, providing an electroneutral KHCO3 secretion pathway. These findings reveal new K þ balance mechanisms that drive adaption to alkaline and K þ -rich foods, which should guide new treatment strategies for K þ disorders.

Original languageEnglish (US)
Pages (from-to)F377-F393
JournalAmerican Journal of Physiology - Renal Physiology
Issue number3
StatePublished - Sep 2023


  • KCC3a
  • alkalosis
  • pendrin
  • potassium secretion
  • renal outer medullary K channels-epithelial Na channels

ASJC Scopus subject areas

  • Urology
  • Physiology


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