Pendrin regulation is prioritized by anion in high-potassium diets.

The Cl^-/[Formula: see text] exchanger pendrin in the kidney maintains acid-base balance and intravascular volume. Pendrin is upregulated in models associated with high circulating aldosterone concentration, such as dietary NaCl restriction or an aldosterone infusion. However, it has not been established if pendrin is similarly regulated by aldosterone with a high-K⁺ diet because the effects of accompanying anions have not been considered. Here, we explored how pendrin is modulated by different dietary potassium salts. Wild-type (WT) and aldosterone synthase (AS) knockout (KO) mice were randomized to control, high-KHCO₃, or high-KCl diets. Dietary KCl and KHCO₃ loading increased aldosterone in WT mice to the same extent but had opposite effects on pendrin abundance. KHCO₃ loading increased pendrin protein and transcript abundance. Conversely, high-KCl diet feeding caused pendrin to decrease within 8 h of switching from the high-KHCO₃ diet, coincident with an increase in plasma Cl^- and a decrease in [Formula: see text]. In contrast, switching the high-KCl diet to the high-KHCO₃ diet caused pendrin to increase in WT mice. Experiments in AS KO mice revealed that aldosterone is necessary to optimally upregulate pendrin protein in response to the high-KHCO₃ diet but not to increase pendrin mRNA. We conclude that pendrin is differentially regulated by different dietary potassium salts and that its regulation is prioritized by the dietary anion, providing a mechanism to prevent metabolic alkalosis with high-K⁺ base diets and safeguard against hyperchloremic acidosis with consumption of high-KCl diets.NEW & NOTEWORTHY Regulation of the Cl^-/[Formula: see text] exchanger pendrin has been suggested to explain the aldosterone paradox. A high-K⁺ diet has been proposed to downregulate a pendrin-mediated K⁺-sparing NaCl reabsorption pathway to maximize urinary K⁺ excretion. Here, we challenged the hypothesis, revealing that the accompanying anion, not K⁺, drives pendrin expression. Pendrin is downregulated with a high-KCl diet, preventing acidosis, and upregulated with an alkaline-rich high-K⁺ diet, preventing metabolic alkalosis. Pendrin regulation is prioritized for acid-base balance.