Molecular biology of the renin-angiotensin system.

T he renin-angiotensin system is one of the major regulators of blood pressure and fluid and electrolyte homeostasis. Its primary components are 1) angiotensinogen, a large globular protein that serves as the substrate for 2) renin, the enzyme that catalyzes the proteolytic conversion of angiotensinogen to the decapeptide angiotensin I; 3) angiotensin converting enzyme, a dipeptidyl carboxypeptidase that converts angiotensin I to the octapeptide angiotensin II; 4) angiotensin II itself; and 5) the angiotensin II receptor, responsible for transducing the cellular effects of angiotensin II (Figure 1). Binding of the final product of this enzymatic cascade (angiotensin II) to its receptor mediates vasoconstriction and aldosterone and catecholamine release, as well as drinking, secretion of prolactin and adrenocorticotrophic hormone, and glycogenolysis.' Historically, this hormonal system has been viewed as a systemic one, the various components of which were derived from different organs and were delivered to their site of action by the circulatory system. More recent evidence using molecular and biochemical approaches to angiotensin physiology raises the possibility that there are distinct, local renin-angiotensin systems with different mechanisms of regulation. Local reninangiotensin systems have been proposed in the vasculature,2 brain,3 heart,4 and kidney,5 but incontrovertible evidence for the existence of all components of the system in physiologically relevant amounts and relationships remains elusive. Although the role of these putative local systems is unknown, it is interesting to speculate that they may serve as a mechanism for limiting the actions of angiotensin II to a specific organ system or physiological event. Molecular biological and sophisticated biochemical measurements have opened a new era in our understanding of this important hormonal system. Not only have these techniques brought to the forefront the controversy surrounding the anatomic location of the individual components, but they also have provided insight into the regulation of the expression and formation of each protein or peptide and opened new strategies for therapeutic manipulation. The recent cloning of the AT, receptor6,7 and the development of pharmacological agents that distinguish this receptor from the closely related, but structurally distinct, AT2 binding site provide a fertile and relatively unexplored field for