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:
- 金额:$ 78.36万
- 依托单位:
- 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:
- 关键词:AblationAcid-Base EquilibriumAlkalosisAnimalsAnionsApicalBicarbonatesCell membraneCell modelCellular biologyChloridesConsumptionCouplingDataDietDietary PotassiumDistalDistal convoluted renal tubule structureEnsureEquilibriumExcretory functionFoodGenesGenetic TranscriptionGenetically Engineered MouseGitelman syndromeHomeostasisIn VitroIntakeIntercalated CellInvestigationKidneyKnockout MiceKnowledgeLinkMediatingMetabolicModelingMolecularMusNephronsPathway interactionsPersonsPhenotypePhosphorylationPhysiologicalPhysiologyPotassiumProteinsPublic HealthPublishingRegulationRoleSLC12A3 geneSodiumSodium ChlorideSyndromeTestingTextbooksTherapeutic InterventionTranslationsVariantVegetarian dietWild Type Mouseabsorptionapical membranechloride-cotransporter potassiumclinical caredietaryin vitro Modelin vivoinhibitorinnovationinterdisciplinary approachknockout animalmouse modelmultidisciplinarynovelnovel therapeuticspotassium bicarbonatepreservationpreventprogramsresponsesymportertargeted treatmentthiazideurinarywasting
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影响,但潜在的影响
机制仍知之甚少。在此,我们提出一项创新计划来结束这一重大事件
知识差距,建立在我们最近发现的长期受追捧的电中性钾运输的基础上
途径。我们的数据表明,膳食碱性负荷刺激电中性 KCl 的表达
协同转运蛋白 KCC3a (Slc12a6) 与 Cl-/HCO3- 交换器 pendrin (Slc26a4) 平行,位于 B-
插层细胞顶膜和噻嗪类敏感氯化钠 NCC 的活化
(Slc12a3),位于远端曲管。在这里,我们提出了一个总体假设:KCC3a 是
长期以来备受追捧的电中性钾分泌途径,并提出了耦合的新想法
KCC3a、pendrin 和 NCC 之间维持钾和酸碱平衡,以响应
食用碱性和富含钾的食物,但会导致碱中毒时钾的浪费。这个新的
该模型将由多学科专家团队结合最先进的细胞技术进行严格测试
新型基因工程小鼠模型中的生物学和生理表型。目标 1 将测试
假设 KCC3a 因摄入碱性饮食和碱中毒而被激活,以驱动
尿钾排泄。将研究嵌入细胞特异性 KCC3 敲除小鼠以进行 a) 测试
KCC3 对钾平衡和 b) 对 pendrin 介导的 HCO3 分泌的贡献; c) 阐明
KCC3 表达调控的分子机制; c) 测试是否特定于 KCC
抑制剂可防止碱血症时 K+ 的损失。目标 2 将检验 pendrin 与以下物质共同激活的假设:
KCC3a 增加 KHCO3 分泌。将研究 Pendrin 敲除小鼠以确定:
pendrin 对 KCC3a 调节的贡献; b) 解耦的生理后果
运输者。我们还将探讨 KCC3a 是否通过 pendrin 转录的变化来调节 pendrin
涉及细胞内氯离子的变化。目标 3 将检验碱中毒驱动 WNK-SPAK 的假设
介导的 NCC 磷酸化激活确保电中性碳酸氢钾分泌占主导地位
过度产生电钾分泌。新开发的 SPAK 小鼠 DCT 特异性损失和增益
将检查体外细胞模型,以严格测试这一想法并探索其机制。综上所述,这
研究计划应阐明一种新机制来解释 K+ 和酸碱平衡是如何发生的
通过食用碱性和富含钾的食物来保存,这是旧石器时代的典型特征
素食饮食。这项调查也有望改变教科书对泌尿系统的解释
碱中毒中钾的浪费,开辟了新的治疗视野。
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Regulation of Blood Pressure and Salt Balance By Pendrin-Positive Intercalated Cells: Donald Seldin Lecture 2020.
- DOI:10.1161/hypertensionaha.121.16492
- 发表时间:2022-04
- 期刊:
- 影响因子:0
- 作者:Wall SM
- 通讯作者:Wall SM
Renal sodium and magnesium reabsorption are not coupled in a mouse model of Gordon syndrome.
- DOI:10.14814/phy2.13728
- 发表时间:2018-07
- 期刊:
- 影响因子:2.5
- 作者:van Megen WH;Grimm PR;Welling PA;van der Wijst J
- 通讯作者:van der Wijst J
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Eric J Delpire其他文献
Eric J Delpire的其他文献
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{{ truncateString('Eric J Delpire', 18)}}的其他基金
OXGR1 in Renal Intercalated Cells, Salt Transport and Diuretic Efficacy
OXGR1在肾闰细胞、盐转运和利尿功效中的作用
- 批准号:
9913504 - 财政年份:2019
- 资助金额:
$ 78.36万 - 项目类别:
OXGR1 in Renal Intercalated Cells, Salt Transport and Diuretic Efficacy
OXGR1在肾闰细胞、盐转运和利尿功效中的作用
- 批准号:
10250314 - 财政年份:2019
- 资助金额:
$ 78.36万 - 项目类别:
OXGR1 in Renal Intercalated Cells, Salt Transport and Diuretic Efficacy
OXGR1在肾闰细胞、盐转运和利尿功效中的作用
- 批准号:
10067053 - 财政年份:2019
- 资助金额:
$ 78.36万 - 项目类别:
Molecular and Functional characterization of the first known human mutation of the SLC12A2 gene
第一个已知人类 SLC12A2 基因突变的分子和功能特征
- 批准号:
9095807 - 财政年份:2016
- 资助金额:
$ 78.36万 - 项目类别:
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