The involvement of ATP-dependent inhibition of ENaC in ARPKD cystogenesis

ENaC 的 ATP 依赖性抑制参与 ARPKD 囊肿发生

基本信息

  • 批准号:
    9146873
  • 负责人:
  • 金额:
    $ 8.82万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-09-21 至 2018-01-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Polycystic kidney diseases (PKD) are a group of inherited nephropathies characterized by the formation of fluid-filled cysts along the nephron. Autosomal Recessive form of PKD (ARPKD) has an incidence of 1 in 20,000 live births; infants with this disease that survive beyond the perinatal period develop chronic renal failure by adolescence and eventually require kidney transplantation. This proposal focuses on the sodium transport regulation in the renal collecting ducts in ARPKD and potential means of pharmacological intervention with the cysts' progression. Specifically, we have determined that Epithelial Sodium Channels (ENaCs), which are expressed in the collecting ducts and represent the rate-limiting step of sodium reabsorption in this nephron segment, are involved into the process of cystogenesis in the ARPKD setting. Our preliminary data indicate that ENaC expression and activity are significantly lower in the cystic epithelial cells of a rat model of ARPKD, as assessed with immunohistochemistry and single channel analysis in isolated cysts; furthermore, chronic administration of the ENaC-specific inhibitor, benzamil, aggravated cyst formation. Thus, we propose that ENaC inhibition exacerbates PKD progression. Using a novel enzymatic microbiosensors approach we established that concentration of adenosine triphosphate (ATP) was significantly higher in PCK rat cortical cysts compared to control rats. ATP was shown to inhibit ENaC via signaling cascades initiated by binding to its receptors. Therefore, we hypothesize here that accumulation of excessive levels of ATP in the lumen of the dilated collecting ducts affects specific purinergic receptors in the cystic cells (primary candidates being P2Y2 or P2X7) and results in ENaC inhibition; this suppresses normal sodium reabsorption in these collecting ducts, and thus promotes fluid accumulation and cysts' expansion. The integrative experimental approach used in this study will include single nephron electrophysiology, in vivo animal studies, genetics, biochemistry, biosensors amperometry and confocal microscopy and will address the clinically relevant problem of cyst expansion in ARPKD. Specifically, this proposal will identify the involvement of the ATP- triggered signaling into regulation of sodium reabsorption in this setting. This proposal will address the following specific aims: 1. Determine the relationship between ENaC activity and cystogenesis in ARPKD; 2. Elucidate the cellular and molecular mechanism by which excessive levels of ATP modulate sodium transport, promoting cyst growth; and 3. Explore if P2 receptor agonists/antagonists and suppression of the ATP levels can affect cystogenesis.
 描述(由申请人提供):多囊肾病(PKD)是一组遗传性肾病,其特征是沿着肾单位形成充满液体的囊肿。常染色体隐性 PKD (ARPKD) 的发病率为 20,000 名活产儿中就有 1 人;患有这种疾病的婴儿在围产期过后存活下来,到青春期就会出现慢性肾功能衰竭,最终需要肾移植。该提案的重点是 ARPKD 肾集合管中钠转运的调节以及对囊肿进展进行药物干预的潜在方法。具体来说,我们已经确定,上皮钠通道(ENaC)在集合管中表达,代表该肾单位段钠重吸收的限速步骤,参与 ARPKD 环境中的囊肿发生过程。我们的初步数据表明,通过免疫组织化学和单通道分析对分离的囊肿进行评估,在 ARPKD 大鼠模型的囊性上皮细胞中,ENaC 的表达和活性显着降低;此外,长期服用ENaC特异性抑制剂苯扎米尔会加剧囊肿形成。因此,我们认为 ENaC 抑制会加剧 PKD 进展。使用新型酶微生物传感器方法,我们确定与对照大鼠相比,PCK 大鼠皮质囊肿中三磷酸腺苷 (ATP) 的浓度显着更高。 ATP 被证明可以通过与其受体结合引发的信号级联抑制 ENaC。因此,我们假设扩张的集合管管腔中过量的 ATP 积累会影响囊性细胞中的特定嘌呤能受体(主要候选者是 P2Y2 或 P2X7)并导致 ENaC 抑制;这会抑制这些集合管中正常的钠重吸收,从而促进液体积聚和囊肿扩张。本研究中使用的综合实验方法将包括单肾单位电生理学、体内动物研究、遗传学、生物化学、生物传感器电流分析法和共聚焦显微镜,并将解决 ARPKD 囊肿扩张的临床相关问题。具体来说,该提案将确定 ATP 触发信号在这种情况下参与钠重吸收的调节。该提案将解决以下具体目标: 1. 确定 ARPKD 中 ENaC 活性与囊肿发生之间的关系; 2. 阐明过量ATP调节钠转运、促进包囊生长的细胞和分子机制; 3.探讨P2受体激动剂/拮抗剂和ATP水平的抑制是否会影响囊肿发生。

项目成果

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Daria Ilatovskaya其他文献

Daria Ilatovskaya的其他文献

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{{ truncateString('Daria Ilatovskaya', 18)}}的其他基金

Improving awareness of women with hypertension: ROAR (Rural, Obese, At Risk) Career Enhancement Core
提高女性高血压患者的意识:ROAR(农村、肥胖、高危)职业提升核心
  • 批准号:
    10714535
  • 财政年份:
    2023
  • 资助金额:
    $ 8.82万
  • 项目类别:
Mitochondria-mediated effects and therapeutic potential of Atrial Natriuretic Peptide in salt-sensitive hypertension
心房钠尿肽在盐敏感性高血压中的线粒体介导作用和治疗潜力
  • 批准号:
    10676800
  • 财政年份:
    2020
  • 资助金额:
    $ 8.82万
  • 项目类别:
Mitochondria-mediated effects and therapeutic potential of Atrial Natriuretic Peptide in salt-sensitive hypertension
心房钠尿肽在盐敏感性高血压中的线粒体介导作用和治疗潜力
  • 批准号:
    10442162
  • 财政年份:
    2020
  • 资助金额:
    $ 8.82万
  • 项目类别:
Mitochondria-Mediated Effects and Therapeutic Potential of Atrial Natriuretic Peptide in Salt-Sensitive Hypertension Diversity Supplement
盐敏感性高血压多样性补充剂中心房钠尿肽的线粒体介导作用和治疗潜力
  • 批准号:
    10337412
  • 财政年份:
    2020
  • 资助金额:
    $ 8.82万
  • 项目类别:
Mitochondria-mediated effects and therapeutic potential of Atrial Natriuretic Peptide in salt-sensitive hypertension
心房钠尿肽在盐敏感性高血压中的线粒体介导作用和治疗潜力
  • 批准号:
    10472035
  • 财政年份:
    2020
  • 资助金额:
    $ 8.82万
  • 项目类别:
The involvement of ATP-dependent inhibition of ENaC in ARPKD cystogenesis
ENaC 的 ATP 依赖性抑制参与 ARPKD 囊肿发生
  • 批准号:
    10419229
  • 财政年份:
    2018
  • 资助金额:
    $ 8.82万
  • 项目类别:

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