While elevated plasma prorenin levels are commonly found in diabetic patients and correlate with microvascular complications, the pathological role of these increases, if any, remain unclear. (Pro)renin binding to the (pro)renin receptor enhances efficiency of angiotensinogen cleavage by renin and unmasks prorenin catalytic activity. We asked whether plasma prorenin could be activated in local vascular tissue through receptor binding. Immunohistochemical staining showed that (pro)renin receptor present in the aorta localized to vascular smooth muscle cells (VSMCs). After cultured rat VSMCs were incubated with 10^-7M inactive prorenin, cultured supernatant acquired the ability to generate Ang I from angiotensinogen indicating that prorenin had been activated. Activated prorenin facilitated angiotensin generation in cultured VSMCs when exogenous angiotensinogen was added. siRNA against the (pro)renin receptor blocked this activation and subsequent angiotensin generation. Prorenin alone induced dose- and time-dependent increases in mRNA and protein for the profibrotic molecule, PAI-1, effects that were blocked by siRNA but not by the Ang II receptor antagonist saralasin. When both inactive prorenin and angiotensinogen were incubated with cells, PAI-1 mRNA increased a striking 54-fold, 8-fold higher than the increase seen with prorenin alone. PAI-1 protein increased 2.75-fold. These effects were blocked by co-treatment with siRNA and saralasin. We conclude that prorenin at high concentration binds the (pro)renin receptor on VSMCs and is activated. This activation leads to increased expression of PAI-1 via Ang II-independent and Ang II-dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may contribute to the progression of fibrotic disease.