Mice Lacking Endothelial ACE

Abstract

Abstract-Recently, the concept of local renin-angiotensin systems (RAS) capable of generating angiotensin II apart from the circulation has received considerable attention. To investigate this, we generated ACE 1/3 mice in which one allele of ACE is null and the second allele was engineered to express ACE on the surface of hepatocytes. ACE 1/3 mice express no endothelial ACE and lack ACE within the lungs. Their kidneys contain Ͻ7.8% the enzyme levels present in control mice. Plasma conversion of angiotensin I to angiotensin II was 43.3% normal. The baseline blood pressure and renal function of the ACE 1/3 mice were normal, probably as a function of a marked increase of both plasma angiotensin I and angiotensin II. When exposed to 2 weeks of a salt-free diet (a stress diet stimulating the RAS), blood pressure in ACE 1/3 mice decreased to 92.3Ϯ2.0 mm Hg, a level significantly lower than that of wild-type control mice. The ACE 1/3 mice demonstrate the plasticity of the RAS and show that significant compensation is required to maintain normal, basal blood pressure in a mouse with an impaired local vascular and renal RAS. Key Words: mice, knockout Ⅲ angiotensin-converting enzyme Ⅲ angiotensin II Ⅲ endothelium Ⅲ blood pressure T he renin-angiotensin system (RAS) is a principle regulator of blood pressure and electrolyte homeostasis within the body. Inhibitors of this system have found broad use in the modern treatment of hypertension, congestive heart failure, and diabetic nephropathy. The RAS was originally characterized as a circulating, endocrine network, but in recent years the concept of a local RAS has gained considerable attention. In part, this is due to the finding that multiple organs express all of the components necessary to recapitulate a functional, local RAS in situ. [1][2][3][4][5] Although in theory, multiple tissues may regulate the production of angiotensin II independent from the circulation, the physiological and pathophysiological role of tissue RAS in organs such as the kidney and the vasculature is not known.Recently, we engineered a mouse with an altered profile in its expression of ACE. 6 This animal, termed ACE.3, does not produce vascular ACE but instead expresses the enzyme on the cell membrane of hepatocytes. This was accomplished by using targeted homologous recombination to substitute the control of ACE expression from its endogenous promoter to an albumin promoter. 7 As such, the liver of the homologous recombinant mouse (termed ACE 3/3 to indicate two targeted alleles) produces 87-fold more ACE than that of a wild-type animal. The only extrahepatic source of tissue ACE in the ACE 3/3 mouse is in the kidney, which has roughly 14% of wild-type levels. This expression is limited to the proximal tubule and is not observed within renal vascular endothelium or adventitia. This residual ACE expression is probably due to the specificity of the albumin promoter, since the original characterization of albumin promoter cassettes similar to that used in the ACE 3/3 mice showed low levels of repor...

Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden Death

“…A similar conclusion was reached in a previous mouse model we studied, termed ACE 1/3, in which ACE expression was predominantly restricted to the liver. 27 Thus, it seems that the plasticity of the RAS (and the plasticity of overall blood pressure control) is such that an animal can adapt to pleomorphic expression patterns of ACE. Finally, we observed normal renal function in the ACE 8/8 mice, despite a complete absence of renal ACE.…”

A highly sensitive immunofluorometric assay for the measurement of aldosterone in small sample volumes: validation in mouse serum

“…There is a discrepancy in the levels of aldosterone which have been reported so far in mice (Takaya et al 2001, Cole et al 2003, Cassis et al 2005, Kessler et al 2005, Cao et al 2006, Makhanova et al 2006. This problem arises from the variability in the assays commercially available for aldosterone measurement and the antibodies utilized.…”

“…However, genetically altered animal models which are of increasing importance for intervention studies and to establish a genotypephenotype relationship are restricted to the mouse (Peters et al 1999, Berger et al 2000, Takaya et al 2001, Cole et al 2003, Jensen et al 2004, Vinson 2004, Kessler et al 2005, Lee et al 2005, Billet et al 2006, Cao et al 2006, Makhanova et al 2006. Currently, there is a lack of longitudinal and systematic studies addressing adrenal gland growth and function as well as circulating aldosterone concentrations in mouse models.…”

Establishing the Role of Angiotensin-Converting Enzyme in Renal Function and Blood Pressure Control through the Analysis of Genetically Modified Mice

“…In these mice, the "1" ACE allele is null, whereas the "3" ACE allele directs ACE expression to the liver. Because of the null allele, ACE 1/3 mice have half of the hepatic, renal, and plasma levels of ACE found in ACE 3/3 mice (20). As compared with wild-type mice, ACE 1/3 mice have only 7% normal renal ACE activity.…”

“…lacks enzymatic activity in one of the two ACE catalytic domains (the N-terminal domain), have a normal BP (17). ACE 1/3 mice, animals with no endothelial expression of ACE and renal levels approximately 7% those of wild-type mice, also have a normal BP (20). Even an animals that are engineered to express ACE only in myocardium and lung smooth muscle (ACE 8/8) present with a BP not much different from that of wild-type mice (21).…”