EPITHELIAL SODIUM CHANNEL GENE PRODUCTS IN SALT SENSITIVE HYPERTENSION

最近，两种形式的人类遗传性高血压被描述出来， 两者都表现出对盐的敏感性。这些遗传缺陷涉及a) 醛固酮的过度产生和b)异常的上皮性钠通道。 完全了解这些基因异常的原因和原因 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。研究最广泛的动物模型是Dahl SS/JR大鼠；其近亲Dahl SR/JR大鼠不发生高血压 吃高盐饮食。我们已经获得了初步数据，表明 高血压前期Dahl S大鼠的内髓集合管细胞， 在滤膜上培养时，吸收的钠是内髓的两倍 收集Dahl R大鼠培养的导管细胞。醛固酮对钠的兴奋作用 S和R单分子膜均可转运，但刺激作用更大 在S的单层膜中。这一观察结果与以下观点是一致的： (不恰当地)S肾脏对钠的吸收增加起到了作用 在高血压的发展中起着至关重要的作用。离子的分析 这些细胞的运输系统表明，较高的Na S膜的转运在很大程度上是由于钠的进入速率较大 穿过管腔(根尖)膜进入细胞。分子途径 涉及的是一个钠通道，很可能与已发现的相同 人类高血压的一种遗传形式的缺陷(利德尔~S 综合症)。这一钠通道可被Aidosterone等调节 肾上腺皮质类固醇。拟议的工作将检验这一假说。 达尔、S和R大鼠之间的遗传差异是导致 钠通道功能的差异。这方面的三个具体方面 本课程将讨论一般假设。首先，我们将确定是否有任何 编码钠通道亚单位的3个基因与 F2代人群中的高血压。第二，我们将确定在多大程度上 其中3个亚基的mRNA受肾上腺类固醇激素的调节。在 同时我们将确定类固醇激素在多大程度上调节 这些亚基在S株和R株之间存在差异。第三，我们将研究 新培育的同源基因大鼠品系中钠转运的某些方面。 该菌株有来自R鼠的11β-羟基酶基因重叠 关于S大鼠的遗传背景。使用这个模型，我们将能够 解决(遗传)异常的机制的重要方面 类固醇的产生有助于增强钠的转运，并有助于 高血压的发病机制。这些实验的结果将 提供有关遗传机制的重要信息 肾脏钠转运率升高的原因及见解 关于这些异常导致 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.