| * BACKGROUND. Renin-angiotensin (Ang) system (RAS) blockers are widely used for the treatment of cardiovascular diseases, and exert beneficial effects in heart, vessel wall and kidney. It is generally believed that these effects are due to interference with Ang II generated at tissue sites. Since the renin that is required for such local Ang II synthesis is derived from the kidney, tissues need to sequester renin (and/or its inactive precursor, prorenin) from the circulation. Nguyen et al. (J Clin Invest 2002) recently identified a renin receptor that may exert this effect. Binding of renin and prorenin to this receptor in human mesangial cells not only facilitated Ang I production, but also resulted, in an angiotensin-independent manner, in MAP kinase activation, DNA synthesis and plasminogen activator inhibitor-1 (PAI-1) release. * HYPOTHESIS. The renin receptor is the 'missing link' responsible for renin uptake, ultimately leading to tissue Ang II generation. In addition, it allows renin and prorenin to act as agonists, thereby providing a role for prorenin, a molecule that was previously thought to have no function of its own. * AIM. To firmly establish the role of the renin receptor, making use of a recently developed transgenic rat (TGR) that overexpresses the human renin receptor in vascular smooth muscle cells (VSMCs). * METHODS. We will measure tissue renin, Ang I and Ang II in TGR and wildtype (Sprague-Dawley) rats, evaluate the vascular and cardiac function of these animals ex vivo, and quantify renin binding to their aortas. Similar studies will be performed in TGR that simultaneously express human renin (i.e., allowing selective activation of the renin receptor without simultaneous Ang II generation, as human renin does not react with rat angiotensinogen). Furthermore, in cultured VSMCs, we will study the localization of the receptor and the direct and indirect (i.e., via Ang II) effects of prorenin, focusing on MAP kinase activation, DNA synthesis and PAI-1 release. * EXPECTED RESULTS. The data will shed light on the functional importance of the renin receptor, beyond the findings that are currently available in human mesangial cells. In addition to knowledge on the contribution of the receptor to tissue Ang II generation, the data will also reveal whether the direct activation of second messenger systems by renin and prorenin results in synergy or antagonism towards Ang II. This is of particular importance under conditions where high endogenous levels of renin and prorenin occur, e.g., in diabetes, heart failure and renovascular hypertension. Based on these data, the renin receptor may prove to be a new component of the RAS, and as such, provide a potential target for therapeutic agents for the treatment of hypertension and/or heart failure. |
