Gene targeting in physiological investigations: studies of the renin-angiotensin system

Gene targeting using homologous recombination in embryonic stem cells provides an avenue for the direct application of precise molecular genetic interventions to the study of complex systems in whole animals. As such, it represents a powerful approach for physiological investigation. Although its applications in physiology were initially limited because of technical difficulties in performing whole animal experiments in mice, these difficulties have been rapidly overcome, and gene targeting has been used productively in physiological experimentation. Studies have been performed using mice in which genes in the renin-angiotensin system (RAS) have been altered by gene targeting, and these studies illustrate both the feasibility and the utility of this technique for addressing physiological issues. These studies have demonstrated novel roles for the RAS in the development and maintenance of kidney structure and have added to the understanding of how RAS gene products regulate blood pressure and renal function. Finally, these experiments may contribute to understanding how naturally occurring mutations in RAS genes cause hypertension.