ATP1A1-dependent Regulation of Sodium Handling by the Renal Proximal Tubule: Mechanism and Implications in Salt-Sensitivity
肾近端小管钠处理的 ATP1A1 依赖性调节:盐敏感性的机制和影响
基本信息
- 批准号:10474518
- 负责人:
- 金额:$ 34.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-24 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:ATP phosphohydrolaseATP1A1 geneAbbreviationsApicalAttentionBicarbonatesBindingBinding SitesBiochemicalBlood Pressure MonitorsCardiac GlycosidesCardiac MyocytesCardiovascular systemCell Culture TechniquesCell LineCellsChronicClinicalCommunitiesComplexCytoskeletonDevelopmentDiseaseEpidermal Growth Factor ReceptorEpithelial CellsFailureFluid BalanceFoundationsGenerationsGeneticGlomerular Filtration RateHomeostasisHypertensionInvestigationIon PumpsIon TransportKidneyKnock-outLaboratoriesLigandsLipidsMediatingMembrane ProteinsModelingMolecularMolecular ConformationMusMuscle ContractionMutationNa(+)-K(+)-Exchanging ATPaseNatriuresisOrganOuabainPatientsPeptidesPharmacologyPhenotypePhosphotransferasesPhysiologicalPhysiologyProtein IsoformsProteinsProtocols documentationProximal Kidney TubulesReactive Oxygen SpeciesReceptor SignalingRegulationReportingRoleScaffolding ProteinSecond Messenger SystemsSignal TransductionSignaling ProteinSodiumSodium ChlorideTelemetryTestingTextbooksTherapeuticTransactivationWorkanimal tissueblood pressure controlchloride-cotransporter potassiumelectrical potentialepithelial Na+ channelhypertensivein vivoknock-downmouse modelmutantneurotransmissionreceptorreceptor functionrenal epitheliumsalt balancesalt intakesalureticsodium-phosphate cotransporter proteinssrc-Family Kinasessymportertooluptakevirtual
项目摘要
ATP1A1 is the only Na/K-ATPase (NKA) isoform expressed in the kidney. As stated in physiology textbooks,
NKA is the enzymatic machinery that powers energy storage in the form of a transmembrane Na+ gradient, which
is essential for renal salt handling and the control of blood pressure. In the renal proximal tubule (RPT), activation
of NKA-mediated classic ion transport function decreases natriuresis through activation of both basolateral (NKA)
and apical (NHE3) Na+ reabsorption. In contrast, activation of the more recently discovered NKA signaling
function triggers a cellular redistribution of both NKA and NHE3 in RPT cells, which decreases Na+ uptake.
Hence, RPT NKA simultaneously serves two opposing roles in Na+ handling: anti-natriuretic through its classic
ATPase-driven ion transport function, and natriuretic through its more recently recognized receptor/signaling
function. To date, the relative contributions of these two NKA functions to the net RPT Na+ handling in vivo is a
fundamentally and therapeutically essential question that has been virtually impossible to answer. NKA signaling,
which is both distinct and independent from NKA classic enzymatic ion-transporting function, was first brought
to the attention of the scientific community by the work of Dr. Zijian Xie in ouabain-treated cardiac myocytes and
renal epithelial cells. Mechanistically, binding of NKA specific ligands such as the cardiotonic steroid (CTS)
ouabain activates Src, resulting in the activation of multiple protein/lipid kinases and the generation of
intracellular second messengers. Numerous groups around the world have expanded the concept of non-
enzymatic signaling function of NKA, while we have focused on the mechanism by which NKA is engaged in
direct interaction with several signaling and scaffolding proteins including Src. This has allowed us to develop
ATP1A1 mutants with intact enzymatic function but defective ability of interaction with signaling partners.
Critically, we have developed a hypomorphic mouse (RPTα1-/-) with a RPT-specific reduction of 70% of NKA α1.
The hyper-reabsorptive renal phenotype of this mouse suggests that NKA signaling is not only physiologically
relevant, but also functionally prevalent in the regulation of RPT Na+ handling. We have established feasibility of
RPT-specific rescue of the hypomorphic RPTα1-/- mouse with either wild-type or Src-binding null mutant forms
of NKA, and propose to use those new tools to test the central hypothesis that NKA α1 (ATP1A1) exerts a tonic
inhibition of apical NHE3 and basolateral Na+ transporters in the RPT. We further surmise that this regulatory
mechanism has a prevalent regulatory role in RPT Na+ handling (Aim 1), depends on NKA α1/Src interaction
(Aim 2), and enables NKA α1 ligands such as CTS to modulate RPT Na+ reabsorption (Aim 3).
Successful completion of the proposed investigation shall reveal a hitherto unrecognized regulatory mechanism
of salt handling by RPT NKA α1, the molecular basis of this regulation, an integrated compensatory transport
network, and their impact on renal physiology and the development of salt sensitivity.
ATP 1A 1是肾脏中表达的唯一Na/K-ATP酶(NKA)同种型。正如生理学教科书中所说,
NKA是以跨膜Na+梯度的形式为能量储存提供动力的酶机制,
对于肾盐处理和血压控制至关重要。在肾近曲小管(RPT)中,激活
NKA介导的经典离子转运功能通过激活基底外侧(NKA)
和顶端(NHE 3)Na+重吸收。相反,最近发现的NKA信号的激活
功能触发RPT细胞中NKA和NHE 3的细胞再分布,这降低了Na+摄取。
因此,RPT NKA在Na+处理中同时发挥两种相反的作用:通过其经典的抗利尿钠作用,
ATP酶驱动的离子转运功能,以及通过其最近认可的受体/信号传导的利钠剂
功能迄今为止,这两种NKA功能对体内RPT Na+净处理的相对贡献是
这是一个根本的、治疗上至关重要的问题,几乎不可能回答。NKA信号,
首次提出了与NKA经典酶离子转运功能不同且独立的功能
谢子健博士在哇巴因治疗的心肌细胞中的工作引起了科学界的注意,
肾上皮细胞从机制上讲,NKA特异性配体如强心类固醇(CTS)
哇巴因激活Src,导致多种蛋白质/脂质激酶的激活和
细胞内第二信使世界各地的许多团体已经扩大了非-
NKA的酶信号传导功能,而我们专注于NKA参与的机制,
与包括Src在内的几种信号和支架蛋白直接相互作用。这使我们能够发展
ATP 1A 1突变体具有完整的酶功能,但与信号伴侣相互作用的能力有缺陷。
重要的是,我们已经开发出一种亚型小鼠(RPTα1-/-),其RPT特异性NKA α1减少70%。
该小鼠的高重吸收肾表型表明NKA信号传导不仅在生理上是
相关,但在RPT Na+处理的调节中也在功能上普遍存在。我们已经确定了
RPT特异性拯救野生型或Src结合无效突变型亚纯型RPTα1-/-小鼠
的NKA,并建议使用这些新工具来测试NKA α1(ATP 1A 1)发挥补品作用的中心假设
抑制RPT中的顶端NHE 3和基底外侧Na+转运蛋白。我们进一步保证,
在RPT Na+处理中,NKA α1/Src相互作用是一种普遍的调节机制(Aim 1
(Aim 2),并使NKA α1配体,如CTS调节RPT Na+重吸收(目的3)。
成功完成拟议的调查将揭示一个迄今为止尚未得到承认的监管机制
盐处理的RPT NKA α1,这种调节的分子基础,一个完整的补偿运输
网络,以及它们对肾脏生理和盐敏感性发展的影响。
项目成果
期刊论文数量(0)
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Sandrine V Pierre其他文献
Sandrine V Pierre的其他文献
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{{ truncateString('Sandrine V Pierre', 18)}}的其他基金
ATP1A1-dependent Regulation of Sodium Handling by the Renal Proximal Tubule: Mechanism and Implications in Salt-Sensitivity
肾近端小管钠处理的 ATP1A1 依赖性调节:盐敏感性的机制和影响
- 批准号:
10280368 - 财政年份:2021
- 资助金额:
$ 34.18万 - 项目类别:
ATP1A1-dependent Regulation of Sodium Handling by the Renal Proximal Tubule: Mechanism and Implications in Salt-Sensitivity
肾近端小管钠处理的 ATP1A1 依赖性调节:盐敏感性的机制和影响
- 批准号:
10662353 - 财政年份:2021
- 资助金额:
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The Na/K-ATPase receptor function as a novel therapeutic target in myocardial infarction
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9813314 - 财政年份:2019
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