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

Abstract

Background: The urinary potassium excretion machinery is upregulated with increasing dietary potassium, but the role of accompanying dietary anions remains inadequately characterized. Poorly absorbable anions, including HCO3-, are thought to increase K+ secretion through a transepithelial voltage effect. Here we test if they also influence the potassium secretion machinery. Methods: Wild-type mice, aldosterone synthase knockout (AS-KO), or pendrin knockout mice were randomized to control, high KCl, or high KHCO3 diets. The potassium secretory capacity was assessed in balance studies. Protein abundance, modification, and localization of the potassium-secretory transporters were evaluated by western blot and confocal microscopy. Results: Feeding the high KHCO3 diet increased urinary K+ excretion and the trans-tubular K+ gradient significantly more than the high KCl diet, coincident with more pronounced upregulation of ENaC and ROMK and apical localization in the distal nephron. Studies in AS-KO mice revealed that the enhanced effects of bicarbonate were aldosterone-independent. The KHCO3 diet also uniquely increased the BK potassium channel b4 subunit, stabilizing BKa on the apical membrane, the Cl/HCO3 exchanger, pendrin, and the apical KCl cotransporter (KCC3a), all of which are expressed specifically in pendrin-positive IC cells. Studies in pendrin KO mice revealed that pendrin was required to increase K+excretion with the KHCO3 diet. In summary, bicarbonate stimulates potassium excretion beyond a poorly-absorbable anion effect, upregulating ENaC and ROMK in principal cells and BK, pendrin, and KCC3a in PP-ICs. The adaptive mechanism prevents hyperkalemia and alkalosis with the consumption of alkaline-ash-rich diets but may drive potassium wasting and hypokalemia in alkalosis.

The K–Cl cotransporter-3 in the mammalian kidney

“…Although, as just discussed, the K þ loss is often associated with K þ channel activity like ROMK in principal cells, a recent study demonstrated that pendrin was required for K þ excretion under a high KHCO 3 diet [46]. In our recent study, we hypothesized that pendrin and KCC3a are functionally coupled (Fig.…”

Horses for Courses: What is the Best Oral Potassium Supplementation Strategy?

“…There is also recent evidence that alkalosis can stimulate KHCO 3 secretion by intercalated cells, through the combined action of pendrin and the KCl cotransporter KCC3a. 9…”

“…There is also recent evidence that alkalosis can stimulate KHCO 3 secretion by intercalated cells, through the combined action of pendrin and the KCl cotransporter KCC3a. 9 In hypokalemia, the goal of K 1 supplementation is clear: to raise plasma [K 1 ]. In a cardiovascular context, it is not known whether the increased cellular uptake and excretion by the kidneys with K citrate supplements are desirable.…”