EPITHELIAL SODIUM CHANNEL GENE PRODUCTS IN SALT SENSITIVE HYPERTENSION

最近，两种形式的人类遗传性高血压已经被描述， 两者都显示盐敏感性。这些遗传缺陷涉及a） 醛固酮的过度产生和B）异常的上皮Na通道。 完全理解这些基因异常 产生高血压才刚刚开始。很可能动物模型 将有助于解开盐的遗传决定因素 敏感性高血压最广泛研究的动物模型是达尔 SS/Jr大鼠;其亲缘动物Dahl SR/Jr大鼠不发生高血压 吃高盐饮食。我们获得的初步数据表明， 高血压前Dahl S大鼠的内髓集合管细胞， 当在过滤器上培养时，吸收的Na是内髓的两倍 从Dahl R大鼠培养的集合管细胞。醛固酮刺激钠 运输的S和R单层，但刺激更大 在S单层中。这一观察结果与以下观点一致： （不适当地）S肾钠吸收率升高起着重要作用。 在高血压的发展中起着至关重要的作用。离子分析 这些细胞的运输系统表明，较高的钠速率， S单分子膜的迁移主要是由于Na的进入速率较大 穿过腔（顶）膜进入细胞。的分子途径 涉及的是钠通道，可能与已发现的相同， 人类高血压的一种遗传形式存在缺陷（Liddle~s 综合征）。该Na通道可由醛固酮和其他调节剂调节。 肾上腺皮质类固醇拟议的工作将检验假设 Dahl S和R大鼠之间的遗传差异 Na通道功能的差异。这三个具体方面 将讨论一般假设。首先，我们将确定 编码Na通道亚基的3个基因与 F2人群高血压。其次，我们将确定 其中3个亚基的mRNA受肾上腺类固醇调节。在 同时，我们将确定在何种程度上类固醇激素调节 这些亚基在S和R菌株之间不同。第三，我们将研究 钠转运在一个新开发的同类大鼠品系的某些方面。 该菌株具有来自R大鼠的11 β-羟化酶基因， S鼠的遗传背景使用这个模型，我们将能够 解决机制的重要方面，使（遗传）异常 类固醇的产生有助于增强钠的转运， 高血压的发病机制这些实验的结果将 提供了关于遗传机制的重要信息 促进肾脏Na转运速率升高， 至于这些异常导致 高血压

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.