EPITHELIAL SODIUM CHANNEL GENE PRODUCTS IN SALT SENSITIVE HYPERTENSION

盐敏感性高血压中的上皮钠通道基因产物

基本信息

批准号：
6302402
负责人：
JOHN B STOKES
金额：
$ 19.94万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-02-01 至 2001-01-31
项目状态：
已结题

项目摘要

Recently, two forms or genetic hyperrension in humans have been described, both of which display salt sensitivity. These genetic defects involve a) overproduction of aldosterone and b) an abnormal epithelial Na channel. The complete understanding of how and why these genetic abnormalities produce hypertension is just beginning. It is likely that animal models will assist in the unraveling of the genetic determinants of salt sensitive hypertension. The most widely studied animal model is the Dahl SS/Jr rat; its relative, the Dahl SR/Jr rat does not develop hypertension eating a high salt diet. We have obtained preliminary data indicating that the inner medullary collecting duct cells of prehypertensive Dahl S rats, when cultured on filters, absorb twice as much Na as inner medullary collecting duct cells cultured from Dahl R rats. Aldosterone stimulates Na transport by both the S and R monolayers, but the stimulation is greater in S monolayers. This observation is consistent with the idea that an (inappropriately) elevated rate of Na absorption by S kidneys plays a crucial role in the development of hypertension. The analysis of the ion transport systems of these cells indicates that the higher rate of Na transport by S monolayers is largely due to the greater rate of Na entry into the cell across the luminal (apical) membrane. The molecular pathway involved is a Na channel, probably the same as has been discovered to be defective in one of the genetic forms of human hypertension (Liddle~s Syndrome). This Na channel can be regulated by aidosterone and other adrenocortical steroids. The proposed work will examine the hypothesis that genetic differences between the Dahl S and R rats are responsible for the differences in Na channel function. Three specific aspects of this general hypothesis will be addressed. First, we will determine if any of the 3 genes encoding the subunits of the Na channel cosegregate with hypertension in F2 populations. Second, we will determine the extent to which the mRNA for the 3 subunits is regulated by adrenal steroids. At the same time we will determine to what extent steroid - hormone regulation of these subunits differs between the S and R strains. Third, we will study certain aspects of Na transport in a newly developed congenic rat strain. This strain has the 11 beta-hydroxylase gene from the R rat superimposed on the S rat genetic background. Using this model, we will be able to address important aspects of the mechanism whereby (genetically) abnormal steroid production contributes to enhanced Na transport and to the pathogenesis of hypertension. The results of these experiments will provide important information regarding the genetic mechanisms contributing to elevated rates of Na transport by the kidney and insights as to the mechanisms whereby these abnormalities contribute to hypertension.

最近，已经描述了人类的两种形式或遗传性超压。两者都表现出盐的敏感性。这些遗传缺陷涉及a）醛固酮和b）异常上皮NA通道的过量生产。完全理解这些遗传异常的方式以及为什么产生高血压才刚刚开始。动物模型可能将有助于解散盐的遗传决定因素敏感的高血压。研究最广泛的动物模型是Dahl SS/JR RAT;它的亲戚DAHL SR/JR大鼠不会出现高血压吃高盐饮食。我们获得了初步数据，表明内部髓质收集型前dahl s大鼠的管道细胞，当在过滤器上培养时，吸收NA的两倍是内髓从Dahl R大鼠培养的管道细胞。醛固酮刺激Na S和R单层的运输，但刺激更大在S单层中。这种观察与一个想法是一致的（不适当）S肾脏的Na吸收速率升高为A 在高血压发展中的关键作用。离子的分析这些单元的运输系统表明NA的速率较高 S单层运输很大程度上是由于NA进入的速度较高穿过腔（顶端）膜进入细胞。分子途径涉及的是一个NA频道，可能与发现的相同在人类高血压的遗传形式之一中有缺陷（Liddle〜S 综合征）。该NA通道可以由辅助酮和其他肾上腺皮质类固醇。拟议的工作将检查假设 Dahl S和R大鼠之间的遗传差异负责 NA通道函数的差异。这三个特定方面将解决一般假设。首先，我们将确定是否有编码Na通道的亚基的3个基因 F2种群中的高血压。第二，我们将确定这3个亚基的mRNA受肾上腺类固醇调节。在同时，我们将确定类固醇 - 激素调节的程度这些亚基在S和R菌株之间有所不同。第三，我们将学习在新开发的先天大鼠菌株中，NA运输的某些方面。该菌株具有从R大鼠叠加的11个β-羟化酶基因在S大鼠遗传背景上。使用此模型，我们将能够解决（遗传上）异常的机制的重要方面类固醇产生有助于增强的NA运输和高血压的发病机理。这些实验的结果将提供有关遗传机制的重要信息肾脏和见解的NA运输速率提高关于这些异常有助于的机制高血压。