The pathophysiological study of pregnancy induced hypertension in transgenic mice carrying both human renin and angiotensinogen genes

人肾素和血管紧张素原基因转基因小鼠妊娠高血压综合征的病理生理学研究

• 批准号: 15591790
• 负责人: MIFUNE Hiroharu
• 金额: $ 2.18万
• 依托单位: Kurume University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591790/
• 关键词: pregnancy-induced hypertension; transgenic mouse; rennin angiotensin system; antihypertension; quinapril; candesartan cilexetil; hydralazine; nicardipine; ヒトレニン遺伝子導入マウス; ヒトアンギオテンシノーゲン遺伝子導入マウス; レニン-アンギオテンシン系; ACE阻害剤; アンギオテンシン受容体拮抗剤; 妊娠中毒症モデル動物

Objectives : The aim of this study is to analyze pathophysiological changes in pregnancy-induced hypertension (PIH) by cross-mating transgenic mice carrying the human-angiotensinogen gene with mice bearing the human-renin gene. Further, we examined antihypertensive effects of four drugs in PIH model mice.Materials and Methods : The systolic blood pressure was measured by the tail-cuff method during the early, mid, and late periods of pregnancy in the transgenic mice and the wild type as control mice. The fetus, placenta, maternal kidney, heart and blood were obtained from the pregnant mice on 18^<th> day of gestation, and then the concentrations of human(h)-renin and angiotensin (AT) II in those materials were measured by radioimmunoassay. Further, the changes of systolic blood pressure and fetal weight in PIH model mice after oral administration of quinapril, candesartan cilexetil, hydralazine and nicardipine were analyzed.Results : In the transgenic mice, the systolic blood pressure began to rise at mid period of gestation, and reached high level in the day before delivery. The hypertension during pregnancy returned to healthy level after delivery. The kidney and fetal weight in the transgenic mice were significantly lower than those in the wild type, but there was no difference in the heart and the placental weight. The hypertension and lower fetal weigh in PIH model mice were improved by oral administration of quinapril and candesartan cilexetil. In the transgenic mice, the h-renin was only detected in the placenta and maternal plasma, and the concentrations of the placental and plasma AT II were significantly higher than those in control mice.Conclusions : Our study showed that the redundant increase of the concentrations of the placental and plasma h-renin and AT II caused hypertension in late period of pregnancy in the transgenic mice.

目的：研究携带人血管紧张素原基因的转基因小鼠与携带人肾素基因的小鼠杂交后妊高征（PIH）的病理生理变化。进一步，我们检测了四种药物对PIH模型小鼠的降压作用。材料与方法：采用尾袖法测定转基因小鼠和野生型小鼠妊娠早、中、后期的收缩压。在妊娠第18天取孕鼠的胎儿、胎盘、母肾、心脏和血液，用放射免疫法测定这些材料中人肾素(h)和血管紧张素（AT） II的浓度。进一步分析口服喹普利、坎地沙坦西列地酯、肼拉嗪和尼卡地平对PIH模型小鼠收缩压和胎儿体重的影响。结果：转基因小鼠的收缩压在妊娠中期开始升高，在分娩前一天达到较高水平。妊娠期高血压在分娩后恢复到健康水平。转基因小鼠的肾脏和胎儿重量明显低于野生型，但心脏和胎盘重量无显著差异。口服喹普利和坎地沙坦西列地酯可改善妊高征模型小鼠的高血压和降低胎儿体重。在转基因小鼠中，h-肾素仅在胎盘和母体血浆中检测到，且胎盘和血浆AT II浓度显著高于对照小鼠。结论：我们的研究表明，胎盘和血浆h-肾素和AT II浓度的过量增加导致转基因小鼠妊娠后期高血压。