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

本课题的重要研究成果将在以下两部分进行总结。肾素-血管紧张素系统是一种酶级联反应，从其前体血管紧张素原中，通过其生理上无活性的中间产物十肽血管紧张素I，产生一种有效的血管收缩剂八肽血管紧张素II。在本研究中，我们利用小鼠胚胎干细胞同源重组产生了血管紧张素原缺陷小鼠。这些小鼠在肝脏中不产生血管紧张素原，导致血浆免疫反应性血管紧张素i完全丧失。纯合突变小鼠的收缩压为66.9 <正负> 4.1 mmHg，明显低于野生型小鼠（100.4 <正负> 44 mmHg）。这种血管紧张素原缺乏小鼠的深度低血压表明肾素-血管紧张素系统在维持血压方面发挥了不可或缺的作用(2)胎盘肾素和母体血管紧张素诱导的妊娠小鼠高血压孕妇高血压是妊娠的常见并发症，其病理生理机制尚不清楚。这种现象在动物模型中通过交配表达人肾素-血管紧张素系统成分的转基因小鼠进行了研究。当表达血管紧张素原的转基因雌性与表达肾素的转基因雄性交配时，由于胎盘分泌的人肾素进入母体循环，怀孕雌性在妊娠后期出现了短暂的血压升高。分娩后血压恢复到正常水平。组织病理学检查显示肾小球均匀增大，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。

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.