ANG II/AT1 RECEPTORS WITH PET

描述(摘自申请者摘要)：肾素-血管紧张素 血管紧张素转换酶系统(RAS)在血液生理调控中起着基础性作用 压力和液体的动态平衡和系统活性的增加可以 对许多疾病的病理生理学有贡献，包括 高血压。RAS的一个关键调节因素是饮食中的Na+；Na+限制 激活RAS，而Na+负荷有相反的作用。虽然 关于饮食中钠离子对肾脏影响的文献很多。 狗的血流动力学，对其对肾脏的影响知之甚少 DAT1受体。这个项目的总体目标是调查 膳食Na+调控对大鼠脑内钙分布及调控的影响 犬肾脏血管紧张素II受体的正电子研究 发射断层扫描(PET)及其与生化指标的相关性 肾皮质和肾组织中DAT1蛋白和mRNA的表达分析 延髓。PET研究将使用一种新的放射性配体[C-11]L-159,884， 它是一种AT1特异性受体拮抗剂。这项提议旨在 测试狗饮食中钠的变化会导致 肾DAT1受体在转录和/或转录水平的调节变化 翻译后水平和体内结合参数 [C-11]L-159,884在肾脏中反映了这些变化。具体目标是： [C-11]L-159,884结合参数的测定和定量 基线条件下活体肾脏正电子发射计算机断层显像(目标1)及研究 低钠饮食(目标2)和高钠饮食(目标3)对心脏功能的影响 DAT1受体的调节。此外，DAT1的mRNA水平将是 肾脏受体结合特性的定量与比较 皮质和髓质，将允许研究潜在的 组织特异性和/或翻译后调控机制在 RAS中的变化。这些实验可以提供第一个活体实验 AT1表达的组织特异性调控机制的证据。 在狗和人中，血管紧张素II(Ang II)作用于 体液动态平衡和心血管功能是通过AT1介导的 基因与啮齿动物不同，啮齿动物拥有两种截然不同和不同的 调节的AT1受体亚型。因此，这只狗之所以被选中，是因为DAT1 受体是研究人类AT1受体的优秀模型。调查 对狗的AT1受体的调节是使用这种方法的第一步 无创PET技术检测人类AT1受体，因此，这 研究最终可能会使我们更好地理解对 在生理和病理生理条件下的人类AT1受体， 例如人类高血压疾病和充血性心力衰竭。

DESCRIPTION (Adapted from Applicant's Abstract): The renin-angiotensin system (RAS) plays a fundamental role in the physiological control of blood pressure and fluid homeostasis and increased activity of the system can contribute to the pathophysiology of numerous disorders including essential hypertension. A key regulator of RAS is dietary Na+; Na+ restriction activates the RAS, while Na+ loading has the opposite effect. Although extensive literature exists on the effects of dietary Na+ on renal hemodynamics in the dog, very little is known about its effects on renal dAT1 receptors. The overall goal of this project is to investigate the effects of dietary Na+ manipulation on the distribution and regulation of type-1 angiotensin II receptors in the canine kidney (dAT1) with positron emission tomography (PET) and correlate the PET findings with biochemical analysis of dAT1 protein and mRNA expression in the renal cortex and medulla. PET studies will employ a novel radioligand, [C-11]L-159,884, which is an AT1 specific receptor antagonist. This proposal is designed to test the hypothesis that alterations in dietary sodium in dogs result in regulatory changes in dAT1 renal receptors at the transcriptional and/or posttranslational level and that in vivo binding parameters of [C-11]L-159,884 in the kidney reflect these changes. The specific aims are: To measure and quantitate binding parameters of [C-11]L-159,884 in the kidney with PET in vivo under baseline conditions (Aim 1) and to investigate the effects of low Na+ diet (Aim 2) and high Na+ diet (Aim 3) on the regulation of dAT1 receptors. In addition, dAT1 mRNA levels will be quantitated and compared with receptor binding characteristics in the renal cortex and medulla which will permit investigation of potential tissue-specific and/or post-translational regulatory mechanisms during alterations in the RAS. These experiments could provide the first in vivo evidence of tissue-specific regulatory mechanisms governing AT1 expression. In both dogs and humans, the effect of angitensin II (Ang II) action on fluid homeostasis and cardiovascular function is mediated through one AT1 gene in contrast to rodents which possess two distinct and differentially regulated AT1 receptor subtypes. Thus, the dog was chosen because the dAT1 receptor is an excellent model for the human AT1 receptor. Investigations of the regulation of AT1 receptors in the dog is a first step in using this non-invasive PET technique to examine human AT1 receptors and thus, this research may ultimately lead to a greater understanding of the regulation of human AT1 receptors under physiological and pathophysiological conditions, such as human hypertensive disorders and congestive heart failure.