Introduction 1 2 3 4 5 6 7 Origin and regulation of prorenin 1 3 8 9 Enzymatic activity of prorenin? 10 10 Prorenin receptor(s)? 11 12 14 15 16 17 15 17 Angiotensin-independent effects of prorenin? 18 18 19 20 1 15 21 21 22 Fig. 1 Model depicting prorenin activation by the (pro)renin receptor (P)RR, allowing prorenin to generate angiotensin I from angiotensinogen. In addition, prorenin binding to the receptor results in effects (intracellular signaling) that are independent of angiotensin generation. HRP is assumed to block both prorenin activation and the direct prorenin-induced effects (see text for further explanation)  23 24 25 26 17 27 Prorenin and renin inhibition 10 28 29 30 Conclusion After many years, it now seems that a function for prorenin has been found. The ‘inactive’ renin precursor gains Ang I-generating activity by binding to a receptor, without undergoing proteolytic cleavage. This mechanism explains how prorenin might contribute to tissue angiotensin generation, even when no prorenin–renin conversion occurs outside the kidney. Renin inhibitors will bind to such open activated prorenin, to the same degree as they bind to renin, and may thus be the ideal tools to block tissue angiotensin generation. In vitro studies suggest that prorenin also acts as an agonist of the (pro)renin receptor, inducing intracellular signaling pathways in an angiotensin-independent manner. However, given the contradictory data obtained with the (pro)renin receptor blocker HRP, more work is needed to verify the in vivo importance of such prorenin-induced (pro)renin receptor activation.