Molecular mechanism of hypertension on pregnant transgenic mice.

(1)筑波高血压小鼠作为人类恶性高血压模型肾素-血管紧张素系统在高血压中起关键作用。我们培育了筑波高血压小鼠（THM，一种携带人类肾素和血管紧张素原基因的转基因小鼠），以便在各种病理条件下进一步检查肾素-血管紧张素系统。我们通过形态计量学、免疫组织化学和超结构方法评估了这些小鼠和对照组肾脏病变的发展。THM组小鼠血压明显高于对照组小鼠；出生一年后，大约高出40毫米汞柱。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%。肾脏血管病变的等级和纤维样动脉炎的发生频率与肾小球硬化指数表现出相同的趋势。光镜和电镜显示THM患者有明显的肾纤维蛋白样动脉炎和“洋葱皮”，两者都是恶性肾硬化的典型症状。THM可能是人类恶性高血压的良好模型。(2)高血压转基因小鼠血管重构我们从生理和组织病理学上分析了高血压转基因小鼠（THM）的血管损伤和血管重构。由于肾素血管紧张素系统（RAS）增强，青春期（8周大）THM已经有高血压，与成年THM的血压相似。它们逐渐发展成显著的血管肥大，包括胸主动脉血管平滑肌细胞（VSMCs）的去分化和细胞外基质的积累，而VSHC增生主要发生在腹主动脉。因此，THM是研究RAS增强介导的血管重构的一个有用的动物模型。

(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.