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Molecular biological studies on regulatory systems of the circulation in angiotensinogen gene knockout mice.

血管紧张素原基因敲除小鼠循环调节系统的分子生物学研究。

基本信息

批准号：
08407020
负责人：
UMEMURA Satoshi
金额：
$ 18.69万
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 (A)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

项目摘要

To clarify the role of renin angiotensin system (RAS) in the regulation of circulating system, in vivo and in vitro studies were performed using angiotensinogen gene knockout mice (Atg ィイD1-ィエD1/ィイD2-ィエD2 ) and it's control mice (Atg ィイD1+ィエD1/ィイD2+ィエD2 ).(1) Hormonal and electrochemical changes, evalated in the Atg ィイD1+ィエD1/ィイD2+ィエD2 and Atg ィイD1-ィエD1/ィイD2-ィエD2 mice fed salt restricted or salt loading diets as well as normal salt diet, suggested the essential role of RAS in the blood pressure maintenance as well as water electrolyte homeostasis.(2) In the kidney of Atg ィイD1-ィエD1/ィイD2-ィエD2, we found renal vessel specific changes, such as hyperplasia and/or hypertrophy of vascular smooth muscle cells, multi-layered elastic reduplication in the intima and media of renal vessels, and increasing renin containing cells, suggesting the important role of RAS in the normal differentiation and development of the kidney.(3) Neuronal type of nitric oxide synthase (N-NOS) in the macula densa of Ang ィイD1-ィエD1/ィイD2-ィエD2 mice is upregulated and inversely regulated by salt intake and this enzyme activity is functionally linked to renal renin production.(4) In Atg ィイD1-ィエD1/ィイD2-ィエD2 mice, lack of Ang II may upregulated ATィイD21ィエD2-R through translational and/or posttranslational mechanisms in Atg ィイD1-ィエD1/ィイD2-ィエD2 mice.(5) Studies on stretch-induced MAP kinase activation in Atg ィイD1+ィエD1/ィイD2+ィエD2 cardiac myocytes suggested the importance of cardiac RAS, although Ang II is not indispensable for mechanical stretch-induced activation of MAP kinases in Atg ィイD1-ィエD1/ィイD2-ィエD2 cardiac myocytes. Furthermore we found that cytokine gp 130 may play a role in the stretch-induced MAP kinase activation independently of Ang II in cardiac myocyte.

为阐明肾素血管紧张素系统（RAS）在循环系统调节中的作用，采用血管紧张素原基因敲除小鼠（Atg β D1-RAS D1/RAS D2-RAS D2）及其对照小鼠（Atg β D1+ RAS D1/RAS D2+ RAS D2）进行了体内外研究。(1)激素和电化学的变化，评估在Atg的RISK D1+ RISK D1/RISK D2+ RISK D2和Atg的RISK D1-RISK D1/RISK D2-RISK D2小鼠喂养盐限制或盐负荷饮食以及正常盐饮食，表明RAS在血压维持以及水电解质稳态的重要作用。(2)在Atg受体D1-Atg受体D1/Atg受体D2-Atg受体D2的肾脏中，我们发现了肾血管特异性的改变，如血管平滑肌细胞增生和/或肥大，血管内膜和中膜的多层弹性复制，含肾素细胞增多，提示RAS在肾脏的正常分化和发育中起重要作用。(3)Ang Ⅱ D1-Ang Ⅱ D1/Ang Ⅱ D2-Ang Ⅱ D2小鼠致密斑中神经元型一氧化氮合酶（N-NOS）被盐摄入量上调和反向调节，该酶活性在功能上与肾肾素产生相关。(4)在AtgイD1-D1/イD2-D2小鼠中，缺乏Ang II可能通过AtgイD1-D1/イD2-D2小鼠的翻译和/或翻译后机制上调ATイD21 D2-R。(5)对拉伸诱导的Atg血管紧张素D1+ Atg血管紧张素D1/Atg血管紧张素D2+ Atg血管紧张素D2心肌细胞中MAP激酶激活的研究表明，心脏RAS的重要性，尽管Ang II不是机械拉伸诱导的Atg血管紧张素D1-Atg血管紧张素D1/Atg血管紧张素D2-Atg血管紧张素D2心肌细胞中MAP激酶激活所必需的。此外，我们发现细胞因子gp 130可能在牵张诱导的心肌细胞MAP激酶激活中起作用，而不依赖于Ang II。