Analysis of ACE Knockout Mice

描述（由申请人提供）：血管紧张素转换酶（ACE）是一种将无活性前体血管紧张素I转化为血管紧张素II的肽酶;在调节心血管和肾功能中起关键作用。在过去的4年中，我们继续表征ACE敲除小鼠的生理学。此外，我们使用遗传技术来创建一系列独特的小鼠模型，在非常选定的组织类型中表达ACE。在资助的第一部分中，我们讨论了我们在表征1）无ACE表达和2）ACE表达仅限于选定组织（如肝脏）的小鼠方面的进展。这项工作表明，与预期相反，血管紧张素转换酶的内皮表达是不必要的正常血压和肾浓缩能力。在该基金的第二部分中，我们提供了表征仅在巨噬细胞中表达ACE的小鼠品系（称为ACE 10/10）的初步数据。如在颈动脉损伤模型中测量的，这些动物似乎对血管损伤反应过度。第一个具体目标是继续表征ACE 10/10小鼠的生理学和巨噬细胞功能。ACE 10/10小鼠在巨噬细胞中过度表达ACE; ACE 3/3小鼠没有巨噬细胞ACE。使用这些动物模型，我们建议研究的具体作用，巨噬细胞和内皮细胞ACE生产在两个模型的血管损伤（目的2）和两个模型的进行性肾脏疾病（目的3）。这项工作反映了大量的文献表明血管紧张素II在人体血管和肾脏损伤中的作用。我们希望了解内皮细胞与巨噬细胞ACE对这种损伤的病理生理学的贡献。

DESCRIPTION (provided by applicant): Angiotensin converting enzyme (ACE) is a peptidase that converts the inactive precursor angiotensin I into angiotensin II; it plays a critical role in regulating cardiovascular and renal function. During the last 4 years, we continued to characterize the physiology of ACE knockout mice. Also, we used genetic techniques to create a series of unique mouse models expressing ACE in very selected tissue-types. In the first portion of the grant, we discuss our progress in characterizing mice with 1) no ACE expression, and 2) ACE expression restricted to selected tissues, such as the liver. This work showed that, contrary to expectations, endothelial expression of ACE is not necessary for normal blood pressure and renal concentrating ability. In the second portion of the grant, we present preliminary data characterizing a mouse line engineered to express ACE only in macrophages (called ACE 10/10). These animals appear hyper responsive to vascular injury as measured in a model of carotid injury. The first Specific Aim is to continue to characterize the physiology and macrophage function of the ACE 10/10 mice. ACE 10/10 mice over-express ACE in macrophages; ACE 3/3 mice have no macrophage ACE. Using these animal models, we propose to study the specific role of macrophage and endothelial ACE production in two models of vascular injury (Aim 2) and in two models of progressive renal disease (Aim 3). This work reflects the enormous literature suggesting a role of angiotensin II in both human vascular and renal injury. Our hope is to understand the contributions of endothelium vs. macrophage ACE to the pathophysiology of this injury.