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:
    10280368
  • 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

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是唯一在肾脏中表达的Na/K-ATPase(NKA)亚型。正如生理学教科书中所说的, Nka是以跨膜Na+梯度的形式为能量存储提供动力的酶机械,它 对处理肾脏盐分和控制血压是必不可少的。在肾近端小管(RPT),激活 NKA介导的经典离子转运功能通过激活两侧基底外侧核(NKA)而减少钠尿 顶端(NHE3)Na+重吸收。相反,最近发现的NKA信号的激活 该功能在RPT细胞中触发NKA和NHE3的细胞重新分布,从而减少Na+的摄取。 因此,RPT NKA在钠离子处理中同时起着两个相反的作用:通过其经典的抗钠尿剂 ATPase驱动的离子转运功能,以及最近识别的受体/信号通路的利钠作用 功能。到目前为止,这两个NKA功能对体内净RPT Na+处理的相对贡献是 从根本上和治疗上都是根本无法回答的问题。NKA信令, 它既不同于NKA经典的酶离子转运功能,又不依赖于NKA经典的酶离子转运功能 为引起科学界的注意,谢子健博士在哇巴因治疗心肌细胞和 肾上皮细胞。从机制上讲,NKA特异性配体的结合,如强心类固醇(CTS) 哇巴因激活Src,导致激活多种蛋白质/脂肪激酶,并产生 细胞内的第二信使。世界各地的许多团体都扩大了非 NKA的酶信号转导功能,而我们主要关注NKA参与的机制 直接与几种信号和支架蛋白相互作用,包括Src。这使得我们能够开发出 ATP1A1突变体具有完整的酶功能,但与信号伙伴的相互作用能力存在缺陷。 关键的是,我们已经开发了一种亚型小鼠(rptα1-/-),其rpt特异性减少了nkAα1的70%。 这只小鼠的高再吸收肾脏表型表明,NKA信号不仅在生理上 相关的,但在功能上也普遍存在于RPT Na+处理的调节中。我们已经确定了 Rpt特异性拯救野生型或src结合缺失突变的亚型rptα1-/-小鼠 ,并建议使用这些新工具来检验NKAα1(ATP1A1)发挥强直作用的中心假说 RPT顶端NHE3和基底侧Na+转运体的抑制。我们进一步推测,这一监管机构 机制在RPTNa+处理(Aim 1)中起着普遍的调节作用,依赖于NKAα1/Src的相互作用 (Aim 2),并使CTS等NKAα1配体能够调节RPTNa+重吸收(Aim 3)。 成功完成拟议的调查将揭示一个迄今未被承认的监管机制 盐处理的RPT NKAα1,这一调节的分子基础,一种综合的补偿性运输 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)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Sandrine V Pierre其他文献

Sandrine V Pierre的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:
    10662353
  • 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:
    $ 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:
Acuson Sequoia C512 Echocardiography System
Acuson Sequoia C512 超声心动图系统
  • 批准号:
    7791820
  • 财政年份:
    2010
  • 资助金额:
    $ 34.18万
  • 项目类别:

相似海外基金

Mechanisms of Cell proliferation and tumorigenesis in ATP1A1 gene mutated adrenal cells
ATP1A1基因突变肾上腺细胞增殖及肿瘤发生机制
  • 批准号:
    21K16058
  • 财政年份:
    2021
  • 资助金额:
    $ 34.18万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了