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是肾脏中唯一表达的Na/K-ATPase (NKA)亚型。正如生理学课本上所说,
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
Na/K-ATP酶受体作为心肌梗死的新型治疗靶点
- 批准号:
9813314 - 财政年份:2019
- 资助金额:
$ 34.18万 - 项目类别:
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7791820 - 财政年份:2010
- 资助金额:
$ 34.18万 - 项目类别:
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