INVESTIGATION OF ANG II/AT1 RECEPTORS WITH PET

说明(申请人提供)：血管紧张素II/AT1受体亚型 (AT1受体)在血液的生理调控中起着基础性作用 压力和液体动态平衡和AT1受体功能增强可以 对包括肾血管在内的许多疾病的病理生理学有贡献 高血压。这个项目的总体目标是调查 肾低灌流(两肾一夹模型)对血管紧张素Ⅱ受体1的调节作用 狗的受体(DAT1)。正电子发射断层扫描(PET)获得的数据 将与DAT1蛋白和mRNA的生化分析相关 在肾脏中的表达。 PET研究将使用放射性配体[11C]L-159,884，这是一个AT1 特异性受体拮抗剂。拟议的目标旨在测试 假设肾脏血流动力学变化的主要致病因素 肾动脉狭窄患者DAT1受体表达改变， [11C]L-159,884在肾脏的体内结合参数反映了这些 改变。建议进行正电子发射计算机断层扫描研究以测量体内结合。 [11C]L-159,884犬单侧肾动脉狭窄后 如果不用血管紧张素转换酶抑制剂赖诺普利治疗， 在假手术的动物身上也是如此。此外，DAT1的mRNA水平将是 体外定量及与受体结合特性的比较 肾组织。这将使调查潜在的可能性成为可能 组织特异性和/或转录后调控机制在 RAS中的变化。 拟议中的实验可能提供第一个体内证据 肾血管AT1表达的组织特异性调控机制 高血压。犬AT1受体调控的研究进展 是使用这种非侵入性PET技术检查 人类AT1受体和这项研究最终应该会导致更大的 人血管紧张素Ⅱ受体在生理和生理状态下的调节 病理生理条件。拟议的研究不仅有助于 阐明AT1受体在RVH中的参与，但可能 促进努力区分患有肾血管性高血压的患者 可能从血运重建中受益。

Description (provided by applicant): The angiotensin II/AT1 receptor subtype (AT1 receptor) plays a fundamental role in the physiological control of blood pressure and fluid homeostasis and increased function of the AT1 receptor can contribute to the pathophysiology of numerous disorders including renovascular hypertension. The overall goal of this project is to investigate the effects of renal hypoperfusion (two-kidney one-clip model) on the regulation of the AT1 receptors in dogs (dAT1). Data obtained with positron emission tomography (PET) will be correlated with biochemical analysis of dAT1 protein and mRNA expression in the kidneys. PET studies will employ the radioligand, [11C]L-159,884, which is an AT1 specific receptor antagonist. The proposed aims are designed to test the hypothesis that a major pathogenetic factor of hemodynamic changes in kidneys with renal artery stensosi is altered expression of the dAT1 receptor and that in vivo binding parameters of [11C]L-159,884 in the kidney reflect these changes. PET studies are proposed to measure the in vivo binding of [11C]L-159,884 after creating unilateral renal artery stenosis in dogs with and without treatment with the angiotensin converting enzyme inhibitor, lisinopril, as well as in sham operated animals. In addition, dAT1 mRNA levels will be quantitated in vitro and compared with receptor binding characteristics in renal tissue. This will make it possible to investigate potential tissue-specific and/or post-transcriptional regulatory mechanisms during alterations in the RAS. The proposed experiments could provide the first in vivo evidence of tissue-specific regulatory mechanisms governing AT1 expression in renovascular hypertension. Investigations of the regulation of the AT1 receptor in the dog are a first step toward using this non-invasive PET technique to examine the human AT1 receptor and this research should ultimately lead to a greater understanding of the regulation of human AT1 receptors under physiological and pathophysiological conditions. The proposed studies will not only help elucidate the involvement of AT1 receptors in RVH but will potentially facilitate efforts to differentiate patients with renovascular hypertension who may benefit from revascularization.