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.
ATP1A1 是肾脏中表达的唯一 Na/K-ATP 酶 (NKA) 亚型。正如生理学教科书中所说,
NKA 是一种酶机制,以跨膜 Na+ 梯度的形式为能量储存提供动力,
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两侧基底外侧 (NKA) 来降低尿钠排泄
和顶端 (NHE3) Na+ 重吸收。相反,最近发现的 NKA 信号传导的激活
该功能触发 RPT 细胞中 NKA 和 NHE3 的细胞重新分布,从而减少 Na+ 的吸收。
因此,RPT NKA 在 Na+ 处理中同时发挥两个相反的作用:通过其经典的抗钠尿作用
ATP 酶驱动的离子转运功能,以及通过其最近识别的受体/信号传导实现利尿钠排泄
功能。迄今为止,这两种 NKA 功能对体内净 RPT Na+ 处理的相对贡献是
从根本上和治疗上来说至关重要的问题实际上是不可能回答的。 NKA 信号传导,
它与NKA经典的酶促离子传输功能不同且独立,首次被引入
谢子建博士在哇巴因处理的心肌细胞中的工作引起了科学界的关注
肾上皮细胞。从机制上讲,NKA 特异性配体的结合,例如强心类固醇 (CTS)
哇巴因激活 Src,导致多种蛋白/脂质激酶的激活并产生
细胞内第二信使。世界各地的许多团体都扩展了非非的概念。
NKA 的酶信号传导功能,而我们重点关注 NKA 参与的机制
与包括 Src 在内的多种信号传导和支架蛋白直接相互作用。这使我们能够发展
ATP1A1 突变体具有完整的酶功能,但与信号传导伙伴相互作用的能力有缺陷。
至关重要的是,我们开发了一种亚效型小鼠(RPTα1-/-),其 RPT 特异性减少了 70% 的 NKA α1。
该小鼠的高重吸收肾表型表明 NKA 信号传导不仅在生理学上
相关,而且在 RPT Na+ 处理的调节中也具有功能上的普遍性。我们已经确定了可行性
对具有野生型或 Src 结合无效突变体形式的低等态 RPTα1-/- 小鼠进行 RPT 特异性拯救
NKA 的研究,并建议使用这些新工具来检验 NKA α1 (ATP1A1) 发挥补品作用的中心假设
抑制 RPT 中的顶端 NHE3 和基底外侧 Na+ 转运蛋白。我们进一步推测,这一监管
机制在 RPT Na+ 处理中具有普遍的调节作用(目标 1),取决于 NKA α1/Src 相互作用
(目标 2),并使 NKA α1 配体(例如 CTS)能够调节 RPT Na+ 重吸收(目标 3)。
拟议调查的成功完成将揭示迄今为止未被认可的监管机制
RPT NKA α1 的盐处理,这种调节的分子基础,一种综合补偿运输
网络,及其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:
$ 34.18万 - 项目类别:
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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