INVESTIGATION OF ANG II/AT1 RECEPTORS WITH PET

描述（由申请人提供）：血管紧张素 II/AT1 受体亚型 （AT1受体）在血液的生理控制中起着基础作用 压力和液体稳态以及 AT1 受体功能的增强可以 有助于包括肾血管在内的许多疾病的病理生理学 高血压。该项目的总体目标是调查以下因素的影响： 肾低灌注（两肾一夹模型）对 AT1 的调节 狗的受体（dAT1）。通过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 表达于肾脏。 PET 研究将使用放射性配体 [11C]L-159,884，它是一种 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改变的主要致病因素 肾动脉狭窄导致 dAT1 受体的表达发生改变 [11C]L-159,884 在肾脏中的体内结合参数反映了这些 变化。 PET 研究旨在测量体内结合 [11C]L-159,884 在患有 和 的狗中造成单侧肾动脉狭窄后 未经血管紧张素转换酶抑制剂赖诺普利治疗， 以及假手术动物。此外，dAT1 mRNA 水平将 体外定量并与受体结合特征进行比较 肾组织。这将使调查潜在的 组织特异性和/或转录后调节机制 RAS 的改变。 所提出的实验可以提供第一个体内证据 肾血管中 AT1 表达的组织特异性调节机制 高血压。狗 AT1 受体调节的研究 是使用这种非侵入性 PET 技术检查 人类 AT1 受体，这项研究最终应该会带来更大的结果 了解生理和环境下人类 AT1 受体的调节 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，但有可能 促进区分肾血管性高血压患者 可能会受益于血运重建。

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.