ROLE OF ENAC IN NA EXCRETION--INNER MEDULLARY COLLECTING DUCT AND EPITHELIUM

ENAC在NA排泄中的作用--内髓收集管和上皮

• 批准号: 6327662
• 负责人: JOHN B STOKES
• 金额: $ 16.01万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6327662
• 关键词: adrenal medulla hormone; angiotensin /renin /aldosterone hypertension; apical membrane; dietary sodium; epithelium; excretion; genetically modified animals; laboratory mouse; laboratory rat; nutrition related tag; renal medulla; renal tubular transport; renal tubule; sodium; sodium channel; tissue /cell culture

The general goal of this project is to further understand the regulation and function of the gene products that form the recently discovered epithelial Na channel. the context in which these studies are undertaken relates to the pathogenesis of salt-sensitive hypertension. There are 2 subprojects. The first subproject capitalizes on new information indicating that primary cultures of the renal inner medullary collecting duct from salt-sensitive rates transport substantially more Nathan do these cells cultured from salt-resistant rats. The hypothesis derived from this data is that an abnormality in the epithelial Na channel complex, or in associated regulatory molecules, contributes to the pathogenesis of salt- sensitive hypertension in humans. the experiments are directed at 3 specific aims. The first aim is to determine the effect of physiologic maneuvers known to alter the activity of collecting duct Na transport on the messenger RNA and protein of each of the 3 major subunits. The focus will be on the kidney and uroepithelium, but responses in lung and colon will be measured in order to examine tissue heterogeneity. The second aim is to determine the biophysical properties of the epithelial Na channel as it exists in the apical membrane of inner medullary collecting duct cells from salt- sensitive and salt-resistant rats. the third aim is to determine the effect of overexpressing one or more of the epithelial Nachannel subunits in the inner medullary collecting duct on Na transport. Using transgenic mice, the rate-limiting subunit will be selectively overexpressed and the animals examined for their salt-sensitivity. These experiments will test the hypothesis that an overactive Na channel in the inner medullary collecting duct will contribute to salt-sensitive hypertension. The second subproject is based on the new observation that the uroepithelium contains epithelial Nachannel subunits. The experiments proposed in this portion will test the hypothesis that these subunits serve a different function that they do in the collecting duct. Rather than participate in Na reabsorption, the hypothesis is that they participate in activation of mechanosensitive nerve fibers. In the renal pelvis, afferent nerve activity is markedly activated by an increase in renal pelvic pressure. Preliminary data suggest that the epithelial Nachannel subunits participate in this activity. the specific aims are to determine the mechanisms by which ameliorate modulates the activation of afferent renal nerve activity. to determine the extent to which ameliorate inhibits the release of putative mediators of mechanoreceptor activation, and to determine the effect of elimination of one of the subunits in genetically altered mice on the activation of afferent renal nerve activity. These experiments will test a novel hypothesis which may have important implications for an interaction of Na channel function and the central nervous system.

该项目的一般目标是进一步了解 构成最近形成的基因产物的调节和功能 发现上皮NA通道。 这些研究的背景 进行的与盐敏感的发病机理有关 高血压。 有2个子标题。 第一个子标记 利用新信息，表明 肾脏内髓质收集导管的盐敏感性 运输几乎更多的内森（Nathan）从 耐盐的大鼠。 从该数据得出的假设是 上皮NA通道复合物或相关的异常 调节分子，有助于盐的发病机理 人类敏感的高血压。 实验定向3 具体目标。 第一个目的是确定 已知会改变收集管的活性的生理操作 Na在Messenger RNA上的传输和3个蛋白质的蛋白质 主要亚基。 重点将放在肾脏和巨像上， 但是，将测量肺和结肠的反应 检查组织异质性。 第二个目的是确定 上皮Na通道的生物物理特性存在于 内部髓质收集管细胞的顶膜 敏感和耐盐的大鼠。 第三个目的是确定 过表达一种或多种上皮纳孔的效果 内部髓质收集导管的亚基在NA运输上。 使用转基因小鼠，限制速率亚基将是选择性的 过表达，并检查了动物的盐敏感性。 这些实验将测试过度活跃的NA的假设 内部髓质收集管中的渠道将有助于 盐敏感高血压。 第二个副本是基于新的观察结果 Uroepithelium包含上皮纳孔亚基。 这 本部分提出的实验将检验以下假设。 这些亚基具有与他们在 收集管道。 而不是参与NA的吸收，而是 假设他们参与机械敏感的激活 神经纤维。 在肾脏骨盆中，传入神经活动明显 通过肾脏骨盆压的升高而激活。 初步数据 建议上皮纳孔亚基参与其中 活动。 具体目的是确定机制 改善调节传入肾神经的激活 活动。 确定改善抑制的程度 释放机械感受器激活的推定介体，并释放 确定消除其中一个亚基的影响 在传入肾脏神经激活的基因改变的小鼠 活动。 这些实验将检验一个新的假设，这可能 对NA通道的相互作用具有重要意义 功能和中枢神经系统。