Dietary Anions Control Potassium Excretion: It is More Than a Poorly Absorbable Anion Effect

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