Analysis of ACE Knockout Mice

描述（由申请人提供）：血管紧张素转换酶（ACE）是一种肽酶，可将无活性的前体血管紧张素I转化为血管紧张素II；它在调节心血管和肾脏功能中起关键作用。在过去的4年里，我们继续研究ACE基因敲除小鼠的生理特征。此外，我们使用遗传技术创建了一系列独特的小鼠模型，在非常选定的组织类型中表达ACE。在拨款的第一部分，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，内皮细胞表达的ACE并不是正常血压和肾浓缩能力所必需的。在拨款的第二部分，我们提供了初步数据，描述了一种仅在巨噬细胞中表达ACE的小鼠系（称为ACE 10/10）。这些动物在颈动脉损伤模型中表现出对血管损伤的高度反应。第一个特异性目的是继续表征ACE 10/10小鼠的生理和巨噬细胞功能。ACE 10/10小鼠巨噬细胞中ACE过表达；ACE 3/3小鼠无巨噬细胞ACE。利用这些动物模型，我们拟研究巨噬细胞和内皮细胞ACE生成在两种血管损伤模型（Aim 2）和两种进行性肾脏疾病模型（Aim 3）中的具体作用。这项工作反映了大量的文献表明血管紧张素II在人类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在这种损伤的病理生理中的作用。

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.