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:10662353
- 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 TransportK ATPaseKidneyKnock-outLaboratoriesLigandsLipidsMediatingMembraneMembrane ProteinsModelingMolecularMolecular ConformationMusMuscle ContractionMutationNatriuresisOrganOuabainPatientsPeptidesPhenotypePhosphotransferasesPhysiologicalPhysiologyProtein IsoformsProteinsProtocols documentationProximal Kidney TubulesReactive Oxygen SpeciesReceptor SignalingRegulationReportingRoleScaffolding ProteinSecond Messenger SystemsSignal TransductionSignaling ProteinSodiumSodium ChlorideTechnologyTelemetryTestingTextbooksTherapeuticTransactivationWorkabsorptionanimal tissueblood pressure controlelectrical potentialepithelial Na+ channelhypertensivein vivoknock-downmouse modelmutantneurotransmissionpharmacologicreceptorreceptor functionrenal epitheliumsalt balancesalt intakesalureticsrc-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.
ATP1A1是在肾脏中表达的唯一Na/k-ATPase(NKA)同工型。如生理学教科书所述
NKA是以跨膜Na+梯度的形式为储能供电的酶促机制,
对于肾脏盐处理和控制血压是必不可少的。在肾脏近端管(RPT)中,激活
NKA介导的经典离子传输功能通过激活两种基体(NKA)而下降了Natriuresis
和顶端(NHE3)Na+重吸收。相反,最近发现的NKA信号的激活
功能会触发RPT细胞中NKA和NHE3的细胞重新分布,从而降低Na+摄取。
因此,RPT NKA只是在NA+处理中扮演两个相反的角色:反纳特里赛经典
ATPase驱动的离子传输函数和NATRIETET通过其最近识别的接收器/信号传导
功能。迄今
从根本上讲是基本的基本问题,几乎是不可能回答的。 NKA信号,
它既独特又独立于NKA经典酶促离子传输功能,首先是带来的
Zijian Xie博士在瓦巴因治疗的心肌细胞和
肾上皮细胞。从机械上讲,NKA特异性配体的结合,例如碳差类固醇(CTS)
Ouabain激活SRC,导致多种蛋白质/脂质激酶的激活和产生
细胞内第二使者。世界各地的许多团体都扩展了非 -
NKA的酶促信号传导功能,而我们专注于NKA参与的机制
与包括SRC在内的几种信号传导和脚手架蛋白的直接相互作用。这使我们得以发展
具有完整酶促功能但与信号伴侣相互作用的能力有缺陷的ATP1A1突变体。
至关重要的是,我们已经开发了一只肌型小鼠(RPTα1 - / - ),而RPT特异性降低了70%的NKAα1。
该小鼠的超呼吸肾表型表明NKA信号不仅是物理上的
相关,但在RPT Na+处理的调节中也很普遍。我们确定了
用野生型或src结合零突变体形式的肌电特异性RPTα1-/ - 小鼠的rpt特异性拯救
NKA,并提出使用这些新工具来测试NKAα1(ATP1A1)的中心假设的提议
抑制RPT中顶端NHE3和基底外侧Na+转运蛋白。我们进一步浏览了这种监管
机理在RPT Na+处理中具有普遍的调节作用(AIM 1),取决于NKAα1/SRC相互作用
(AIM 2),并使NKAα1配体(例如CTS)调节RPT Na+重吸收(AIM 3)。
成功完成拟议的调查应揭示隐藏的未识别的监管机制
RPTNKAα1的盐处理,该调节的分子基础,一种综合的代偿运输
网络及其对肾脏生理的影响及其盐敏感性的发展。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Na/K-ATPase signaling tonically inhibits sodium reabsorption in the renal proximal tubule.
Na/K-ATP酶信号强直性抑制肾近曲小管中的钠重吸收。
- DOI:10.1096/fj.202200785rr
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Mukherji,ShreyaT;Brambilla,Luca;Stuart,KaileyB;Mayes,Isabella;Kutz,LauraC;Chen,Yiliang;Barbosa,LeandroA;Elmadbouh,Ibrahim;McDermott,JeffP;Haller,StevenT;Romero,MichaelF;Soleimani,Manoocher;Liu,Jiang;Shapiro,JosephI;Blan
- 通讯作者:Blan
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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:
10474518 - 财政年份:2021
- 资助金额:
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