New approaches to genetic manipulation of mice: tissue-specific expression of ACE

Abstract

. New approaches to genetic manipulation of mice: tissue-specific expression of ACE. Am J Physiol Renal Physiol 284: F599-F607, 2003; 10.1152/ajprenal.00308. 2002The renin-angiotensin system (RAS) plays a central role in body physiology, controlling blood pressure and blood electrolyte composition. ACE.1 (null) mice are null for all expression of angiotensin-converting enzyme (ACE). These mice have low blood pressure, the inability to concentrate urine, and a maldevelopment of the kidney. In contrast, ACE.2 (tissue null) mice produce one-third normal plasma ACE but no tissue ACE. They also have low blood pressure and cannot concentrate urine, but they have normal indices of renal function. These mice, while very informative, show that the null approach to creating knockout mice has intrinsic limitations given the many different physiological systems that no longer operate in an animal without a functioning RAS. To investigate the fine control of body physiology by the RAS, we developed a novel promoter swapping approach to generate a more selective tissue knockout of ACE expression. We used this to create ACE.3 (liver ACE) mice that selectively express ACE in the liver but lack all ACE within the vasculature. Evaluation of these mice shows that endothelial expression of ACE is not required for blood pressure control or normal renal function. Targeted homologous recombination has the power to create new strains of mice expressing the RAS in selected subsets of tissues. Not only will these new genetic models be useful for studying blood pressure regulation but also they show great promise for the investigation of the function of the RAS in complicated disease models.angiotensin-converting enzyme; blood pressure; angiotensin II; liver; renin-angiotensin system ROUGHLY ONE-HALF OF ALL AMERICANS die from cardiovascular disease. Put differently, more Americans die of cardiovascular disease than the next seven leading causes of death combined (1). To understand cardiovascular disease, one must understand how the body regulates blood pressure, a complex process governed by many different components, including multiple vasoconstrictors and vasodilators. Among these is the renin-angiotensin system (RAS), which produces the vasoconstrictor angiotensin II. The basic physiology by which angiotensinogen is degraded to angiotensin II has been known for many years, with the importance of this system underscored by the enormous clinical utility of pharmaceuticals that interrupt angiotensin II formation or action. So with all that is known about the RAS, what could conceivably be new? In fact, the use of targeted homologous recombination in mouse embryonic stem (ES) cells has produced a startling series of insights into the operation and functional importance of the RAS. This progress has been so rapid and dramatic as to implicate the RAS as easily the most important regulator of cardiovascular function as measured through blood pressure control.The use of homologous recombination to modify genes relies on the properties of cul...

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Angiotensin II receptor blockade and insulin sensitivity in overweight and obese adults with elevated blood pressure

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Role of the N-terminal Catalytic Domain of Angiotensin-converting Enzyme Investigated by Targeted Inactivation in Mice

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