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EFFCTS OF ANOVEL NTERACTING MOLECULE OFAT1 RECEPTOR ON RENAL FUNCTION

新型FAT1受体相互作用分子对肾功能的影响

基本信息

批准号：
18590897
负责人：
TAMURA Kouichi
金额：
$ 2.48万
依托单位：
Yokohama City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590897/
关键词：
Signaling Blood pressure regulation Interacting molecule Bioactivity Translational research

项目摘要

Chronic elevations of circulating angiotensin II (Ang II) cause sustained hypertension and enhanced accumulation of intrarenal Ang II by an Ang II type 1 receptor (AT1 receptor) -dependent process. Previous studies showed that the C-terminal cytoplasmic domain of AT1 receptor is involved in the control of receptor internalization and in linking receptor-mediated signal transduction to the specific biological response. We previously cloned a novel molecule ATRAP (AT1 receptor-associated protein) that specifically interacts with C-terminal of AT1 receptor. The results of previous in vitro studies showed that ATRAP specifically inhibits AT1 receptor signaling by constitutive activation of AT1 receptor internalization to decrease cell surface AT1 receptor number. The present study tested the hypothesis that chronic elevations in circulating Ang II regulate ATRAP protein expression in a tissue-specific manner. C57BL6 mice were infused with Ang II (1,000 ng/kg/min)or vehicle subcutaneously f … More or 14 days via osmotic minipump. On day 12, systolic blood pressure averaged 176+/-1.0 mm Hg in Ang II-infused mice compared with mice given vehicle (122+/-4 mm Hg) .Western blot analysis using the anti-AT1 receptor and anti-ATRAP antibodies was performed. The results showed that AT1 receptor protein levels in the kidney and liver were comparable in Ang II- and vehicle-infused mice. In contrast, ATRAP protein levels were significantly decreased in the kidney of Ang II-infused mice (51% decrease; P<0.05). ATRAP protein levels in the liver were also similar in the two groups. Therefore, these "results indicate that renal and liver AT1 receptor gene expression is maintained but renal ATRAP gene expression is specifically suppressed in Ang II-induced hypertension. The renal-specific down-regulation of the ratios of ATRAP/AT1 receptor expression by Ang II infusion causes the relative predominance of AT1 receptor signaling over inhibition by ATRAP in the kidney and thus allows the sustained effects of chronic elevations in Ang II to elicit progressive increases in blood pressure. Less

循环血管紧张素II（Ang II）的慢性升高可引起持续性高血压，并通过Ang II 1型受体（AT 1受体）依赖性过程增加肾内Ang II的蓄积。已有研究表明，AT 1受体的C端胞质结构域参与受体内化的调控，并将受体介导的信号转导与特异性生物学反应联系起来。我们之前克隆了一种新型分子ATRAP（AT 1受体相关蛋白），它与AT 1受体的C末端特异性相互作用。先前的体外研究结果表明，ATRAP特异性抑制AT 1受体信号转导，通过组成性激活AT 1受体内化，减少细胞表面AT 1受体数量。本研究验证了循环血管紧张素II慢性升高以组织特异性方式调节ATRAP蛋白表达的假设。C57 BL 6小鼠皮下注射Ang II（1，000 ng/kg/min）或载体， ...更多信息或14天。在第12天，血管紧张素II输注小鼠的平均收缩压为176+/-1.0 mm Hg，而给予载体的小鼠为122+/-4 mm Hg。结果表明，在肾脏和肝脏中的AT 1受体蛋白水平在血管紧张素II和车辆输注的小鼠是相当的。与此相反，ATRAP蛋白水平在Ang II灌注小鼠的肾脏中显著降低（降低51%; P<0.05）。肝脏中的ATRAP蛋白水平在两组中也相似。因此，这些结果表明，肾脏和肝脏AT 1受体基因表达维持，但肾脏ATRAP基因表达特异性抑制血管紧张素II诱导的高血压。通过血管紧张素II输注的ATRAP/AT 1受体表达比率的肾特异性下调导致AT 1受体信号传导相对于ATRAP在肾中的抑制占优势，从而允许血管紧张素II慢性升高的持续效应引起血压的进行性升高。少