RENAL SODIUM TRANSPORTERS IN CONTROL OF ARTERIAL BLOOD PRESSURE

高血压在美国是一个主要的健康问题， 影响大约四分之一的人口， 中风和肾衰竭 现有证据表明， 调节动脉血压的主要机制在于 肾脏通过以下方式控制细胞外液体积的能力 盐和水排泄的改变。 因此， 介导穿过肾顶膜的钠重吸收 上皮细胞，其中一些作为抗高血压的目标 药物，很可能作为肾脏的组成部分， 调节动脉血压控制的系统。为了验证这一 假设我们建议开发和分析小鼠模型，其中 编码这些转运蛋白的基因被切除。 在目标1中，我们将使用基因 利用靶向技术， 近端小管顶端Na/H交换器，Na，K，2C 1协同转运蛋白 Henle氏粗升支的NaCl 1协同转运蛋白， 曲小管和集合管的Na通道。 的 突变后代的生存力将通过基因型分析进行评估。 频率、胚胎/胎儿发育、出生体重、存活和生长 率和组织组织学，从而允许确定是否 每个转运蛋白都是生存所必需的，或者， 是一种补偿机制， 传送器 在目标2中，我们将确定这些主要遗传基因是否 缺陷，其中编码每一个的基因的一个或两个拷贝， 顶端钠转运蛋白被破坏，能够产生 动脉血压的慢性变化。 通过利用这些 基因改变的动物，其中钠重吸收在个人 肾单位部分已经扰动，这将是可能的评估， 对照中每个转运蛋白和肾单位片段的相对重要性 动脉血压，以及一些肾脏代偿性 机制等 野生型和突变型动物将维持在低水平， 正常和高钠饮食，以及血压的慢性变化 将通过股动脉导管插入术和尾袖进行分析 程序. 肾小球滤过率，肾血浆流量， 血浆容量、Na+和K+的尿排泄、血浆肾素水平和 将评估沿着肾单位的醛固酮和Na，K-ATP酶活性， 和代偿性变化的形态学相关性将通过以下方法进行分析： 电镜 我们预计，小鼠在这种情况下发育， 建议将成为有价值和广泛使用的模型进行详细分析 肾脏钠离子处理与 和动脉血压。

Hypertension is a major health problem in the United States that ultimately affects about one quarter of the population and contributes to heart attacks, stroke, and kidney failure. Available evidence suggests that a major mechanism for the regulation of arterial blood pressure resides in the ability of the kidneys to control extracellular fluid volume by alterations in the excretion of salt and water. Thus, the transporters that mediate sodium reabsorption across the apical membranes of renal epithelial cells, some of which serve as targets for antihypertensive medications, are likely to serve as integral components of the renal systems mediating control of arterial blood pressure. To test this hypothesis we propose to develop and analyze mouse models in which the genes encoding these transporters are ablated. In aim 1 we will use gene targeting technology to develop mice with disruptions of the genes encoding the apical Na/H exchanger of the proximal tubule, the Na,K,2C1cotransporter of the thick ascending limb of Henle, the NaC1 cotransporter of the distal convoluted tubule, and the Na channel of the collecting duct. The viability of mutant offspring will be assessed by analysis of genotype frequency, embryonic/fetal development, birthweight, survival and growth rate, and tissue histology, thereby allowing a determination of whether each transporter is essential for survival or, alternatively, whether there are compensatory mechanisms that overcome the loss of a particular transporter. In aim 2 we will determine whether these primary genetic defects, in which one or both copies of the genes encoding each of the apical sodium transporters has been disrupted, are capable of producing a chronic alteration in arterial blood pressure. By utilizing these genetically altered animals, in which sodium reabsorption in individual nephron segments has been perturbed, it will be possible to assess the relative importance of each transporter and nephron segment in the control of arterial blood pressure, as well as some of the renal compensatory mechanisms. Wild-type and mutant animals will be maintained on low, normal, and high sodium diets, and chronic.alterations in blood pressure will be analyzed by both femoral artery catheterization and tail cuff procedures. Alterations in glomerular filtration rate, renal plasma flow, plasma volume, urinary excretion of Na+ and K+, plasma levels of renin and aldosterone, and Na,K-ATPase activity along the nephron will be assessed, and morphological correlates of compensatory changes will be analyzed by electron microscopy. We anticipate that the mice developed in this proposal will become valuable and widely used models for detailed analysis of the mechanisms underlying the relationship between renal Na+ handling and arterial blood pressure.