REVIEW Exploring type I angiotensin (AT 1 ) receptor functions through gene targeting S. D. Crowley, P.-L. Tharaux, L. P. Audoly and T. M. Coffman Division of Nephrology, Duke University and Durham VA Medical Centers, Durham, NC, USA Received 14 October 2003, accepted 1 March 2004 Correspondence: T. M. Coffman, Building 6/Nephrology, VA Medical Center, 508 Fulton Street, Durham, NC 27705, USA. Abstract The renin–angiotensin system (RAS) modulates a diverse set of physiological processes including development, blood pressure, renal function and in- flammation. The principal effector molecule of this system, angiotensin II, mediates most of these actions. The classically recognized functions of the RAS are triggered via the type 1 (AT 1 ) class of angiotensin receptors. Phar- macological blockade of the AT 1 receptor lowers blood pressure and slows the progression of cardiovascular and renal diseases. Gene-targeting tech- nology provides an experimental approach for precisely dissecting the phy- siological functions of the RAS. Here, we review how gene-targeting experiments have elucidated AT 1 receptor functions. Keywords angiotensin II, AT 1 receptor, gene targeting, hypertension, renin–angiotensin system. Introduction to the renin–angiotensin system and AT 1 receptors The renin–angiotensin system (RAS) is a critical regu- lator of blood pressure, sodium excretion, and water homeostasis. Discovered roughly a century ago by Tigerstedt, an aspartyl protease he named renin triggers the conversion of angiotensinogen to the decapeptide angiotensin-I (Ang I). While a single gene encodes renin in most species, wild mice and some strains of labor- atory mice carry 2 renin genes similar in function but disparate in their patterns of tissue expression. These genes called Ren-1 and Ren-2 likely arose through gene duplication (Piccini et al. 1982, Dickinson et al. 1984). Next in the RAS cascade, angiotensin-converting enzyme (ACE) cleaves Ang I to form octapeptide angiotensin II (Ang II), the primary effector molecule of the RAS. Ang II exerts its effects through G-protein coupled receptors that can be separated into two pharmacolo- gical classes, type I (AT 1 ) and type 2 (AT 2 ) (Timmer- mans et al. 1993). Studies with specific non-peptide antagonists have shown that AT 1 receptors mediate most of the classical effects of the RAS on blood pressure and fluid homeostasis including regulation of tubular glomerular feedback (TGF), stimulation of renal tubular sodium reabsorption, release of aldosterone from the adrenal glomerulosa, vascular smooth muscle contraction, and stimulation of hypothalamic thirst sensors. Two AT 1 receptor isoforms, AT 1A and AT 1B , exist in rodents. However, only a single AT 1 isoform has been confirmed in humans. The murine AT 1 receptors are products of separate genes (Agtr1a and Agtr1b) and share substantial sequence homology (Iwai et al. 1992). AT 1A receptors predominate in most organs, except the adrenal and pituitary glands, where AT 1B receptor expression is appreciable (Gasc et al. 1994). The AT 2 receptor appears to counterbalance the actions of AT 1 receptors with respect to blood pressure and cellular proliferation (Hein et al. 1995, Ichiki et al. 1995, Nakajima et al. 1995, Oliverio et al. 1998a,b). The paramount roles of the RAS in the regulation of blood pressure and kidney function are well-established. Initially, the functions of the various RAS components were tentatively identified using pharmacologic block- ade. However, there are limitations with this type of study. For example, the binding profiles of AT 1A and AT 1B receptors are virtually identical (Iwai et al. 1992), making it difficult to discriminate their in vivo functions pharmacologically. In recent years, each major Acta Physiol Scand 2004, 181, 561–570 Ó 2004 Scandinavian Physiological Society 561