ANG II/AT1 RECEPTORS WITH PET

带有 PET 的 ANG II/AT1 受体

• 批准号: 2749558
• 负责人: ZSOLT SZABO
• 金额: $ 44.7万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2749558
• 关键词: angiotensin II; dietary sodium; dogs; hormone inhibitor; hormone receptor; immunocytochemistry; in situ hybridization; kidney imaging /visualization; kidney metabolism; laboratory rat; magnetic resonance imaging; nutrition related tag; pharmacokinetics; positron emission tomography; posttranscriptional RNA processing; radiotracer; receptor binding; receptor expression; renal cortex; renal medulla; renin angiotensin system; tissue /cell preparation

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.

说明（改编自申请人的摘要）： RAS系统在血液的生理控制中起着重要作用 压力和流体稳态以及系统的增加的活性可 有助于许多疾病的病理生理学， 高血压 RAS的关键调节因子是饮食Na+; Na+限制 激活RAS，而Na+负荷具有相反的效果。 虽然 关于饮食中Na+对肾脏的影响，存在大量文献。 尽管在狗的血液动力学中，关于其对肾脏的影响知之甚少， dAT 1受体。 本项目的总体目标是调查 日粮钠离子调控对细胞内钙离子分布和调节的影响 犬肾血管紧张素II 1型受体（dAT 1）的正电子 发射断层扫描（PET），并将PET结果与生物化学 分析肾皮质中dAT 1蛋白和mRNA的表达， 髓质 PET研究将使用一种新的放射性配体[C-11]L-159，884， 其是AT 1特异性受体拮抗剂。 这项建议旨在 测试狗饮食中钠的改变导致 dAT 1肾受体在转录和/或 翻译后水平和体内结合参数 肾脏中的[C-11]L-159，884反映了这些变化。 具体目标是： 测定并定量[C-11]L-159，884在 在基线条件下（目标1）体内使用PET检查肾脏，并研究 低钠日粮（Aim 2）和高钠日粮（Aim 3）对大鼠小肠肌层的影响 dAT 1受体的调节。 此外，dAT 1 mRNA水平将被 定量并与肾脏中的受体结合特征进行比较 皮质和髓质，这将允许研究潜在的 组织特异性和/或翻译后调节机制 RAS的变化。 这些实验可以提供第一个体内 组织特异性调节机制的证据，管理AT 1的表达。 在狗和人中，血管紧张素II（Ang II）作用对 流体稳态和心血管功能通过一个AT 1介导 与啮齿类动物相比， 调节AT 1受体亚型。 因此，选择犬是因为dAT 1 受体是人AT 1受体的极好模型。 调查 在狗的AT 1受体的调节是第一步， 非侵入性PET技术来检查人类AT 1受体，因此， 研究可能最终导致更好地理解监管， 在生理和病理生理条件下的人AT 1受体， 例如人类高血压疾病和充血性心力衰竭。