RENAL SODIUM TRANSPORTERS IN CONTROL OF ARTERIAL BLOOD PRESSURE

高血压是美国的一个主要健康问题，最终 影响大约四分之一的人口，并对心脏做出贡献 发作、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的能力 盐和水排泄的变化。因此，传送器 通过肾顶膜介导钠的重吸收 上皮细胞，其中一些是抗高血压的靶点 药物，很可能是肾脏不可或缺的组成部分 调节动脉血压的系统。为了测试这一点 假设我们建议开发和分析小鼠模型，在该模型中 编码这些转运蛋白的基因被烧毁。在目标1中，我们将使用基因 利用靶向技术培育基因编码紊乱的小鼠 近曲小管顶端Na/H交换器--Na，K，2C1共转运体 粗大的Henle升支，远端的NaC1共转运体 曲曲的小管和集合管的钠通道。这个 突变后代的生存能力将通过基因分析进行评估。 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 每一个运输者都是生存所必需的，或者，无论有没有 是克服特定损失的补偿机制 传送器。在目标2中，我们将确定这些主要基因 缺陷，其中一个或两个拷贝的基因编码每个 心尖部钠离子转运体被破坏，能够产生 动脉血压的慢性改变。通过利用这些 转基因动物，其中钠在个体中重吸收 肾单位节段受到干扰，将有可能评估 各转运体和肾单位段在控制中的相对重要性 对动脉血压的影响，以及对肾脏的一些代偿 机械装置。野生型和突变型动物将保持在较低的水平， 正常和高钠饮食，以及慢性血压变化 将通过股动脉插管和尾袖进行分析 程序。肾小球滤过率、肾血浆流量、 血浆容量、尿钠、尿钾排泄量、血浆肾素和尿钾水平 将评估沿肾单位的醛固酮和Na，K-ATPase活性， 以及补偿性变化的形态相关性将通过 电子显微镜。我们预计小鼠是在这种情况下发育的 建议将成为有价值和广泛使用的详细分析模型 肾脏钠处理之间关系的潜在机制 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.