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Coordinated SLC12A3/SLC12A6/SL26A4 electroneutral transport pathways maintain K+ homeostasis and acid-base balance

协调的 SLC12A3/SLC12A6/SL26A4 电中性转运途径维持 K 稳态和酸碱平衡

基本信息

批准号：
10735503
负责人：
Eric J Delpire
金额：
$ 78.36万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735503
关键词：
Ablation Acid-Base Equilibrium Alkalosis Animals Anions Apical Bicarbonates Cell membrane Cell model Cellular biology Chlorides Consumption Coupling Data Diet Dietary Potassium Distal Distal convoluted renal tubule structure Ensure Equilibrium Excretory function Food Genes Genetic Transcription Genetically Engineered Mouse Gitelman syndrome Homeostasis In Vitro Intake Intercalated Cell Investigation Kidney Knockout Mice Knowledge Link Mediating Metabolic Modeling Molecular Mus Nephrons Pathway interactions Persons Phenotype Phosphorylation Physiological Physiology Potassium Proteins Public Health Publishing Regulation Role SLC12A3 gene Sodium Sodium Chloride Syndrome Testing Textbooks Therapeutic Intervention Translations Variant Vegetarian diet Wild Type Mouse absorption apical membrane chloride-cotransporter potassium clinical care dietary in vitro Model in vivo inhibitor innovation interdisciplinary approach knockout animal mouse model multidisciplinary novel novel therapeutics potassium bicarbonate preservation prevent programs response symporter targeted treatment thiazide urinary wasting

项目摘要

Alkaline diets and alkalemia have a profound impact on potassium homeostasis, but the underlying mechanisms remain poorly understood. Here we propose an innovative plan to close this significant knowledge gap, building on our recent discovery of a long sought-after electroneutral potassium transport pathway. Our data reveal that dietary alkaline loading stimulates the expression of the electroneutral KCl cotransporter, KCC3a (Slc12a6), in parallel with the Cl-/HCO3- exchanger, pendrin (Slc26a4), on the B- type intercalated cell apical membrane and the activation of the thiazide-sensitive sodium-chloride, NCC (Slc12a3), in the Distal Convoluted Tubule. Here we advance the overarching hypothesis that KCC3a is the long sought-after electroneutral potassium secretory pathway and propose the novel idea that coupling between KCC3a, pendrin, and NCC maintains potassium and acid-base balance in response to the consumption of alkaline and potassium-rich foods but drives potassium wasting in alkalosis. This new model will be rigorously tested by a multidisciplinary team of experts, combining state-of-the-art cellular biology and physiological phenotyping in novel genetically engineered mouse models. Aim 1 will test the hypothesis that KCC3a is activated in response to the consumption of alkaline diets and alkalosis to drive urinary potassium excretion. Intercalated-cell-specific KCC3 knockout mice will be investigated to a) test the contribution of KCC3 to potassium balance and b) to pendrin-mediated HCO3- secretion; c) elucidate the molecular mechanisms that underlie the regulation of KCC3 expression; c) test if KCC-specific inhibitors prevent the loss of K+ in alkalemia. Aim 2 will test the hypothesis that pendrin is co-activated with KCC3a to increase KHCO3 secretion. Pendrin knockout mice will be studied to determine: a) the contribution of pendrin to the regulation of KCC3a; and b) the physiologic consequences of uncoupling the transporters. We will also explore if KCC3a regulates pendrin through changes in pendrin transcription that involve changes in intracellular chloride. Aim 3 will test the hypothesis that alkalosis drives WNK-SPAK mediated phospho-activation of NCC to ensure electroneutral potassium bicarbonate secretion prevails over electrogenic potassium secretion. Newly developed DCT-specific loss and gain of SPAK mice and in vitro cell models will be examined to rigorously test this idea and explore the mechanism. In summary, this program of investigation should illuminate a new mechanism to explain how K+ and acid-base balance are preserved with the consumption of alkaline and potassium-rich foods, typical of the paleolithic and vegetarian diets. The investigation is also expected to change the textbook explanation of urinary potassium wasting in alkalosis, opening a new therapeutic horizon.

碱性饮食和碱血症对钾稳态有深远的影响，但潜在的