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(申请人提供):多囊肾病(PKD)是一组遗传性肾病,其特征是沿肾单位形成充满液体的囊性病变。常染色体隐性遗传性PKD(ARPKD)的发病率为每20,000名活产儿中就有1名;患有这种疾病的婴儿在围产期后存活下来,在青春期后发展为慢性肾衰竭,最终需要肾移植。这项建议侧重于ARPKD患者肾脏集合管中钠的运输调节,以及可能的药物干预手段来控制囊性病变的进展。具体地说,我们已经确定在集合管中表达的上皮性钠通道(ENaCs)代表了肾单位段钠重吸收的限速步骤,参与了ARPKD环境下的囊变过程。我们的初步数据显示,免疫组织化学和单通道分析显示,在ARPKD大鼠模型的囊性上皮细胞中,ENaC的表达和活性显著降低;此外,ENaC特异性抑制剂苯扎米的长期应用加剧了囊性形成。因此,我们认为抑制ENaC会加剧PKD的进展。利用一种新的酶微生物传感器方法,我们发现PCK大鼠皮质囊中三磷酸腺苷(ATP)的浓度明显高于对照组大鼠。研究表明,ATP通过与ENaC受体结合而启动的信号级联反应来抑制ENaC。因此,我们假设,在扩张的集合管的管腔中积累过多的ATP会影响囊性细胞(主要候选为P2Y2或P2X7)中的特定嘌呤能受体,并导致ENaC抑制;这抑制了这些集合管中正常的钠重吸收,从而促进了液体积累和囊泡的扩张。本研究采用的综合实验方法包括单肾单位电生理学、活体动物研究、遗传学、生物化学、生物传感器安培法和共聚焦显微镜,并将解决ARPKD囊性扩张的临床相关问题。具体地说,这项提案将确定在这种情况下,ATP触发的信号参与钠重吸收的调节。该提案将针对以下具体目标:1.确定ARPKD中ENaC活性与囊变的关系;2.阐明过高水平的ATP调节钠转运、促进囊壁生长的细胞和分子机制;3.探索P2受体激动剂/拮抗剂和抑制ATP水平是否会影响囊变。

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
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:
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:
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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