The involvement of ATP-dependent inhibition of ENaC in ARPKD cystogenesis
The involvement of ATP-dependent inhibition of ENaC in ARPKD cystogenesis
批准号:
10419229
负责人:
Daria Ilatovskaya
金额:
$2.11万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-02-15 至 2022-01-31
中文摘要
项目总结
多囊肾病(PKD)是一组遗传性肾病,其特征是形成液性肾小球。
沿肾单位充满了囊泡。常染色体隐性遗传性PKD(ARPKD)的发病率为1/20,000
出生;患有这种疾病的婴儿在围产期后存活下来,会通过以下方式发展为慢性肾衰竭
青春期,最终需要肾移植。这项建议集中在钠的运输上。
ARPKD肾脏集合管的调节及药物干预的可能途径
包囊的进展。具体地说,我们已经确定上皮钠通道(ENaCs),这是
在集合管中表达,代表肾单位钠重吸收的限速步骤
片段,都参与了ARPKD环境下的囊变过程。我们的初步数据显示
在ARPKD、AS模型大鼠的囊性上皮细胞中,ENAC的表达和活性显著降低
用免疫组织化学和单通道分析评估孤立的囊肿;此外,慢性
给予ENaC特异的抑制剂苯扎米,会加剧包囊的形成。使用一种新型的酶
微生物传感器的方法我们建立了三磷酸腺苷(ATP)的浓度显著
与对照组相比,PCK大鼠皮质囊的表达水平更高。三磷酸腺苷通过信号级联途径抑制ENaC
通过与其受体结合而启动。因此,我们在这里假设,过量的
扩张的集合管管腔中的三磷酸腺苷影响囊性细胞和结果中的特定嘌呤能受体
在ENaC抑制中;这抑制了这些收集管道中正常的钠重吸收,并促进了液体
积聚和包囊扩张。本研究中使用的综合实验方法将包括单一的
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
并将解决ARPKD的囊性扩张这一临床相关问题。具体地说,这
提案将确定囊性细胞中参与嘌呤能信号转导的受体,并研究其相关性
依赖于饮食中的钠含量,ATP信号转导钠重吸收。这项提案将解决
具体目的如下:1.明确ARPKD中ENaC活性与囊变的关系;
阐明过量的三磷酸腺苷调节钠转运的细胞和分子机制,
3.探讨P2受体激动剂/拮抗剂及对ATP水平的抑制作用
会影响囊变的发生。
英文摘要
PROJECT SUMMARY
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. 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 hypothesized here that accumulation of excessive levels of
ATP in the lumen of the dilated collecting ducts affects specific purinergic receptors in the cystic cells and results
in ENaC inhibition; this suppresses normal sodium reabsorption in these collecting ducts, and 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 receptors involved in the purinergic signaling in the cystic cells, and study the relevance
of ATP signaling to sodium reabsorption dependent on sodium content in the diet. 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.
期刊论文(8)
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DOI:
10.1177/1470320316653858
发表时间:
2016-07
期刊:
Journal of the renin-angiotensin-aldosterone system : JRAAS
影响因子:
--
作者:
[Pavlov TS, Levchenko V, Ilatovskaya DV, Moreno C, Staruschenko A]
通讯作者:
Staruschenko A
DOI:
10.1016/j.lfs.2015.12.022
发表时间:
2016-08-15
期刊:
Life sciences
影响因子:
6.1
作者:
[Palygin O, Miller B, Ilatovskaya DV, Sorokin A, Staruschenko A]
通讯作者:
Staruschenko A
DOI:
10.14814/phy2.12950
发表时间:
2016-09
期刊:
Physiological reports
影响因子:
2.5
作者:
[Blass G, Levchenko V, Ilatovskaya DV, Staruschenko A]
通讯作者:
Staruschenko A
DOI:
10.3389/fphys.2021.693130
发表时间:
2021
期刊:
Frontiers in physiology
影响因子:
4
作者:
[Vasileva VY, Sultanova RF, Sudarikova AV, Ilatovskaya DV]
通讯作者:
Ilatovskaya DV
DOI:
10.21037/jtd.2016.10.100
发表时间:
2016-10
期刊:
Journal of thoracic disease
影响因子:
2.5
作者:
[A. Staruschenko;D. Ilatovskaya;T. Pavlov]
通讯作者:
A. Staruschenko;D. Ilatovskaya;T. Pavlov
Improving awareness of women with hypertension: ROAR (Rural, Obese, At Risk) Career Enhancement Core
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项目类别:
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Mitochondria-mediated effects and therapeutic potential of Atrial Natriuretic Peptide in salt-sensitive hypertension
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资助金额:$56.94万
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依托单位:
Mitochondria-mediated effects and therapeutic potential of Atrial Natriuretic Peptide in salt-sensitive hypertension
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批准号:10472035
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项目类别:
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资助金额:$52.54万
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依托单位:
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资助金额:$2.7万
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负责人:Daria Ilatovskaya
-
依托单位:
The involvement of ATP-dependent inhibition of ENaC in ARPKD cystogenesis
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批准号:9146873
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项目类别:
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资助金额:$8.82万
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财政年份:2015
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负责人:Daria Ilatovskaya
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