Analysis of ACE Knockout Mice

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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.