Gene-targeting Studies of the Renin-Angiotensin System: Mechanisms of Hypertension and Cardiovascular Disease

As a major regulator of blood pressure in humans, therenin–angiotensin system has been the subject of extensive biochemical, pharmacological, and physiological investigation. The development of efficient approaches forgene targeting in mice has allowed detailed examinationof each component of this highly complex endocrine system. In addition to confirming previous concepts aboutthe functions of this system, genetic manipulation of therenin–angiotensin system has uncovered novel pathwaysin development, hypertension, renal and cardiac function,and immunology. Homologous recombination in embryonic stem cells (Bronson and Smithies 1994) and pronuclear injection of transgenes (Gordon and Ruddle 1981)have both been used to create transgenic mice in whichgenes are "knocked-out" or genetically altered. All majorcomponents of the renin–angiotensin system have beengenetically manipulated in mice, and these animals havebeen used to study the functions of specific candidategenes, both in physiological and pathophysiological conditions. In this paper, we review the results of experiments using these knockout mice, highlighting information revealed by these studies in understanding thephysiological functions of the renin–angiotensin system...