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

本项目的重要研究成果概括为以下两个部分：(1)血管紧张素原缺陷小鼠血压低下肾素-血管紧张素系统是一个酶系统，通过其生理活性不活跃的中间十肽血管紧张素Ⅱ，从其前体血管紧张素原产生一种有效的血管收缩八肽血管紧张素II。在本研究中，我们通过在小鼠胚胎干细胞中进行同源重组来产生血管紧张素原缺陷小鼠。这些小鼠的肝脏不产生血管紧张素原，导致血浆中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&lt；正负4.1毫米汞柱，显著低于野生型小鼠(100.4&lt；正负44毫米汞柱)。肾素-血管紧张素系统在维持血压中起着不可或缺的作用。(2)胎盘肾素和母体血管紧张素致妊娠高血压母体高血压是妊娠期常见的并发症，其病理生理机制尚不清楚。通过与表达人类肾素-血管紧张素系统的转基因小鼠交配，在动物模型中研究了这一现象。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，由于胎盘人肾素分泌到母体循环中，怀孕雌性在妊娠后期表现出一过性的血压升高。幼崽出生后，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，伴有尿蛋白排泄增加、心肌肥大、胎盘坏死和水肿。这些小鼠可能提供对人类妊娠高血压的分子洞察力。

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.