Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States.
Am J Physiol Renal Physiol. 2023 Mar 1;324(3):F256-F266. doi: 10.1152/ajprenal.00128.2022. Epub 2023 Jan 19.
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-KHCO, or high-KCl diets. Dietary KCl and KHCO loading increased aldosterone in WT mice to the same extent but had opposite effects on pendrin abundance. KHCO loading increased pendrin protein and transcript abundance. Conversely, high-KCl diet feeding caused pendrin to decrease within 8 h of switching from the high-KHCO 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-KHCO 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-KHCO 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. 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.
肾脏中的 Cl-/[公式：见文本]交换蛋白 pendrin 维持酸碱平衡和血管内体积。在与循环醛固酮浓度升高相关的模型中，如饮食 NaCl 限制或醛固酮输注，pendrin 上调。然而，尚未确定高钾饮食是否通过醛固酮同样调节 pendrin，因为尚未考虑伴随阴离子的影响。在这里，我们探讨了不同钾盐如何调节 pendrin。野生型（WT）和醛固酮合酶（AS）敲除（KO）小鼠被随机分配到对照、高 KHCO3 或高 KCl 饮食组。饮食 KCl 和 KHCO3 负荷使 WT 小鼠中的醛固酮增加到相同程度，但对 pendrin 丰度的影响相反。HCO3 负荷增加 pendrin 蛋白和转录物丰度。相反，高 KCl 饮食喂养在从高 KHCO3 饮食切换后的 8 小时内导致 pendrin 减少，同时血浆 Cl 增加和[公式：见文本]减少。相比之下，在 WT 小鼠中，将高 KCl 饮食切换至高 KHCO3 饮食会导致 pendrin 增加。AS KO 小鼠的实验表明，醛固酮是最佳上调高 KHCO3 饮食反应中 pendrin 蛋白所必需的，但不是增加 pendrin mRNA。我们得出结论，不同的钾盐以不同的方式调节 pendrin，其调节优先考虑饮食阴离子，从而提供了一种机制来防止高钾碱基饮食引起的代谢性碱中毒，并防止高 KCl 饮食引起的高氯性酸中毒。Cl-/[公式：见文本]交换蛋白 pendrin 的调节已被提出解释醛固酮悖论。高钾饮食被提议下调 pendrin 介导的保钾 NaCl 重吸收途径，以最大限度地增加尿钾排泄。在这里，我们挑战了这一假设，揭示了伴随的阴离子而不是钾驱动 pendrin 表达。高 KCl 饮食下调 pendrin，防止酸中毒，高 K 富碱饮食上调 pendrin，防止代谢性碱中毒。pendrin 调节优先考虑酸碱平衡。
