Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin

The renin-angiotensin system (RAS) is critical for the control of blood pressure and salt balance in mammals. Renin is an aspartyl protease synthesized as prorenin, a proenzyme that contains an additional 43–amino acid N-terminal fragment. The physiological maturation of prorenin into active renin takes place exclusively in the juxtaglomerular cells of the kidney (1). Renin has high substrate specificity, and its only known substrate is angiotensinogen. Renin cleaves the N terminus of circulating angiotensinogen to angiotensin I (Ang I; a decapeptide), which is then transformed in angiotensin II (Ang II; an octapeptide) by soluble or endothelial cell–associated angiotensin-converting enzyme (ACE). In the heart, the majority of Ang I is converted by chymase (2). The rate-limiting step in the RAS is Ang I generation, even though the major biologically active peptide is Ang II. Ang II acts on vascular smooth muscle cells as a potent vasoconstrictor via Ang II receptors. These receptors are widely distributed and expressed by many cell types (3). Components of the RAS and Ang II receptors are found in the brain (4) and in many peripheral tissues such as the heart (5) and kidney (6), but also placenta (7), testis (8), adipose tissue (9), and eye (10, 11). Recent studies have shown that the RAS is involved in diverse physiological and pathological processes such as growth and remodeling (12), development (13), inflammation (14), vascular hypertrophy, and thrombosis (15). If Ang II and Ang IV receptors are well characterized, the demonstration of a functional renin receptor is still missing. Several proteins able to bind renin have been reported. The widely distributed mannose-6-phosphate receptor has been shown to bind renin and prorenin on rat cardiac myocytes (16) and on human endothelial cells (17). Another renin-binding protein called RnBp has been identified in rat, porcine, and human tissues and was shown later to be identical to the N-acyl-D-glucosamine 2-epimerase (18). Several binding sites have also been described on membranes from different rat organs but no functional effects of renin binding were reported (19, 20). In contrast to these studies (19, 20), we have shown that renin could bind to human mesangial cells in culture and that the binding induced an hypertrophic effect and an increase of plasminogen activator inhibitor-1. Renin bound to the receptor was neither internalized nor degraded (21, 22). The receptors of proteases may play several roles. They serve to focus the enzymatic activity on a cell surface or at a cell-extracellular matrix interface, as for urokinase and plasminogen/plasmin (23). The urokinase receptor binds not only the active enzyme but also the inactive proenzyme. The binding of the proenzyme induces a conformational change that unmasks the active site in the absence of proteolytic activation of the proform.