权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Transgenic mice and knock out mice in renin-angiotensin system.

肾素-血管紧张素系统转基因小鼠和基因敲除小鼠。

基本信息

批准号：
06404016
负责人：
MURAKAMI Kazuo
金额：
$ 18.62万
依托单位：
UNIVERSITY OF TSUKUBA
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1996
项目状态：
已结题

项目摘要

The important research results in this project are summarized in the fololowing two sections.(1) Angiotensinogen-Deficient Mice with HypotensionThe renin-angiotensin system is an enzymatic cascade that produces a potent vasoconstrictor octapeptide angiotensin II,through its physiologically inactive intermediate decapeptide angiotensin I,from their precursor angiotensinogen. In the present study, we generated angiotensinogen-deficient mice by homologous recombination in mouses embryonic stem cells. These mice do not produce angiotensinogen in the liver, resulting in the complete loss of plasma immunoreactive angiotensin I.The systolic blood pressure of the homozygous mutant mice was 66.9 <plus-minus> 4.1 mmHg, significantly lower than that of wild-type mice (100.4 <plus-minus> 44 mmHg). This profound hypotension in angiotensinogen-deficient mice demonstrates an indispensable role for the renin-angiotensin system in maintaining blood press(2) Hypertension Induced in Pregnant Mice by Placental Renin and Maternal AngiotensinogenMaternal hypertension is a common complication of pregnancy and its pathophysiology is poorly understood. This phenomenon was studied in an animal model by mating transgenic mice expressing components of the human renin-angiotensin system. When transgenic females expressing angiotensinogen were mated with transgenic males expressing renin, the pregnant females displayd a transient elevation of blood pressure in late pregnancy, due to secretion of placental human renin into the maternal circulation. Blood pressure returned to normal levels after delivery of the pups. Histopathologic examination revealed uniform enlargement of glomeruli associated with an increase in urinary protein excretion, myocardial hypertrophy, and necrosis and edema in the placenta. These mice may provide molecular insights into pregnancy-associated hypertension in humans.

本课题的主要研究成果概括在以下两个部分。(1)血管紧张素原缺乏的低血压小鼠肾素-血管紧张素系统是一种酶级联反应，它通过其生理学上无活性的中间体十肽血管紧张素I，从其前体血管紧张素原产生有效的血管收缩剂八肽血管紧张素II。在本研究中，我们通过小鼠胚胎干细胞同源重组的方法获得了血管紧张素原缺陷小鼠。这些小鼠不产生血管紧张素原在肝脏中，导致血浆免疫反应性血管紧张素I的完全丧失。纯合子突变小鼠的收缩压为66.9 - <plus-minus>4.1毫米汞柱，显着低于野生型小鼠（100.4 <plus-minus>- 44毫米汞柱）。血管紧张素原缺陷小鼠的这种严重低血压证明了肾素-血管紧张素系统在维持血压中不可或缺的作用。（2）胎盘肾素和母体血管紧张素原诱导的妊娠小鼠高血压母体高血压是妊娠的常见并发症，其病理生理学知之甚少。在动物模型中通过交配表达人肾素-血管紧张素系统组分的转基因小鼠研究了这种现象。当表达血管紧张素原的转基因雌性动物与表达肾素的转基因雄性动物交配时，妊娠雌性动物在妊娠后期显示出血压的短暂升高，这是由于胎盘分泌的人肾素进入母体循环。分娩后，血压恢复到正常水平。组织学检查显示肾小球均匀增大，伴有尿蛋白排泄增加、心肌肥大、胎盘坏死和水肿。这些小鼠可能为人类妊娠相关高血压提供分子见解。