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

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-03-01 Epub Date: 2023-01-19 DOI:10.1152/ajprenal.00128.2022
Ebrahim Tahaei, Truyen D Pham, Lama Al-Qusairi, Rick Grimm, Susan M Wall, Paul A Welling
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Abstract

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.

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在高钾膳食中,阴离子优先调节 Pendrin。
肾脏中的 Cl-/[公式:见正文]交换子垂体促肾上腺皮质激素能维持酸碱平衡和血管内容量。在与高循环醛固酮浓度相关的模型中,如饮食NaCl限制或醛固酮输注,pendrin会上调。然而,由于尚未考虑伴随阴离子的影响,因此尚未确定垂体促肾上腺皮质激素是否同样受到高K+饮食中醛固酮的调节。在此,我们探讨了垂体促肾上腺皮质激素如何受不同膳食钾盐的调节。将野生型(WT)和醛固酮合成酶(AS)基因敲除(KO)小鼠随机分为对照组、高KHCO3组和高KCl组。WT小鼠膳食KCl和KHCO3负荷增加醛固酮的程度相同,但对垂体促肾上腺皮质激素丰度的影响相反。KHCO3 负荷增加了垂体蛋白和转录本的丰度。相反,饲喂高KCl饮食会导致垂体促肾上腺皮质激素在从高KHCO3饮食转换到高KHCO3饮食的8小时内减少,这与血浆Cl-的增加和[公式:见正文]的减少相吻合。相反,在 WT 小鼠中,将高 KCl 饮食转换为高 KHCO3 饮食会导致垂体促肾上腺皮质激素增加。AS KO 小鼠的实验表明,醛固酮是上调垂体促肾上腺皮质激素蛋白以应对高 KHCO3 饮食的必要条件,但不是增加垂体促肾上腺皮质激素 mRNA 的必要条件。我们的结论是,垂体促肾上腺皮质激素受不同膳食钾盐的不同调节,而且膳食阴离子优先调节垂体促肾上腺皮质激素,这提供了一种机制,可通过高钾碱膳食防止代谢性碱中毒,并通过食用高氯化钾膳食防止高氯性酸中毒。高K+饮食被认为会降低pendrin介导的K+-节约型NaCl重吸收途径,从而最大限度地增加尿液中K+的排泄。在这里,我们对这一假设提出了质疑,揭示了驱动垂体蛋白表达的是伴随的阴离子,而不是 K+。Pendrin在高KCl饮食中下调,从而防止酸中毒;在富含碱性的高K+饮食中上调,从而防止代谢性碱中毒。Pendrin 的调节优先考虑酸碱平衡。
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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
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