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

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 Ca^{2 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.