Molecular mechanism of hypertension on pregnant transgenic mice.

妊娠转基因小鼠高血压的分子机制。

• 批准号: 09306024
• 负责人: MURAKAMI Kazuo
• 金额: $ 6.91万
• 依托单位: FOUNDATION FOR ADVANCEMENT OF INTERNATIONAL SCIENCE (1999)University of Tsukuba (1997-1998)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09306024/
• 关键词: Tsukuba hypertensive mouse; malignant hypertension; Vascular remodeling; renin-angiotensin system; transgenic mouse; 腎臓; 大動脈瘤; 動脈硬化症; コレステロール; 脂肪; アンギオテンシンII; 受容体; レニン; 高血圧; アンジオテンシノーゲン; 妊娠; トランスジェニックマウス; アンジオテンシンII; 臓器傷害

(1) The Tsukuba hypertensive mouse as a model of human malignant hypertensionThe renin-angiotensin, system has a pivotal role in hypertension. The Tsukuba hypertensive mouse (THM; a transgenic mouse carrying human genes for both renin and angiotensinogen) was generated to allow further examination of the renin-angiotensin system in a variety of pathologic conditions. We evaluated the development of renal lesions in these mice and in controls by morphometric, immunohistochemical and ultra-structural methods. Blood pressure was significantly higher in THM than in control mice; 1 year after birth, it was approximately 40 mmHg higher. The kidney-to-body weight ratio was also higher in THM than in control. Morphometrical analysis revealed that the glomerular sclerosis index was significantly elevated in THM with 10% of the glomeruli sclerotic at 18 months. The grade of vascular lesion and the frequency of fibronoid arteritis of the kidney exhibited the same tendency as the glomerular sclerosis index. Light and electron microscopy revealed significant fibrinoid arteritis of the kidney in THM and also "onion skinning" , both pathognomonic for malignant nephrosclerosis. THM may be an excellent model of human malignant hypertension.(2) Vascular remodeling in hypertensive transgenic miceWe physiologically and histopathologically analyzed vascular damage due to hyper' tension and vascular remodeling in hypertensive transgenic mice (THM). Pubertal(8-week -old) THM already had hypertension similar to blood pressure in adult THM due to an enhanced renin angiotensin system (RAS). They progressively developed remarkable vascular hypertrophy composed of dedifferentiation of vascular smooth muscle cells (VSMCs) and extracellular matrix accumulation in the thoracic aorta, and VSHC hyperplasia was predominant in the abdominal aorta. THM are therefore a useful animal model for studying vascular remodeling mediated by enhanced RAS.

(1)筑波高血压小鼠作为人类恶性高血压模型的研究筑波高血压小鼠（THM;一种携带人肾素和血管紧张素原基因的转基因小鼠）的产生是为了进一步研究各种病理条件下的肾素-血管紧张素系统。我们通过形态计量学、免疫组织化学和超微结构方法评价了这些小鼠和对照组中肾脏病变的发展。THM小鼠的血压明显高于对照组小鼠;出生后1年，血压高出约40 mmHg。THM组的肾体重比也高于对照组。形态计量学分析显示THM组肾小球硬化指数显著升高，18个月时肾小球硬化率为10%。肾血管病变程度和纤维支气管样动脉炎的发生率与肾小球硬化指数的变化趋势一致。光学和电子显微镜检查显示THM患者肾脏出现明显的纤维素样动脉炎以及“洋葱皮”，这两种都是恶性肾硬化症的特征。THM可能是一种很好的恶性高血压动物模型。(2)高血压转基因小鼠血管重构我们对高血压转基因小鼠（THM）高血压引起的血管损伤和血管重构进行了生理学和组织病理学分析。青春期（8周龄）THM由于增强的肾素血管紧张素系统（RAS）已经具有与成人THM中的血压相似的高血压。他们进行性发展显着的血管肥大的血管平滑肌细胞（VSMCs）的去分化和细胞外基质的积累在胸主动脉，和VSHC增生是占主导地位的腹主动脉。因此，THM是研究增强的RAS介导的血管重塑的有用的动物模型。

项目成果

F.Sugiyama et al.: "Speedy backcrossing through in vitro fertilization using prepubertal superovulation and neonatal deth dependent on genetic background in angiotensinogen-deficient mice." Lab.Anim.Sci.47. 545-548 (1997)

F.Sugiyama 等人：“通过利用青春期前超排卵和新生儿死亡的体外受精进行快速回交，这取决于血管紧张素原缺陷小鼠的遗传背景。”

Kihara,M.: "The neuronal isoform of constitutive nitric oxide synthase is upregulated in the macula densa of angiotensinogen gene-knockout mice." Lab.Invest.76. 285-294 (1997)

Kihara,M.：“血管紧张素原基因敲除小鼠的致密斑中，组成型一氧化氮合酶的神经元亚型上调。”

N. Nishijo et al.: "Vascular remodeling in hypertensive transgenic mice"Exp. Anim.. 48. 203-208 (1999)

N. Nishijo 等人：“高血压转基因小鼠的血管重塑”实验。

N.Nishijo et al.: "Salt-sensitive aortic aneurysm and rupture in hypertensive transgenic mice that overproduce angiotensin II."Lab. Invest.. 78. 1059-1066 (1998)

N.Nishijo 等人：“过量产生血管紧张素 II 的高血压转基因小鼠中的盐敏感性主动脉瘤和破裂。”实验室。

N.Nishijo et al.: "Vascular remodeling in hypertensive transgenic mice."Exp. Anim.. 48. 203-208 (1999)

N.Nishijo 等人：“高血压转基因小鼠的血管重塑。”实验。