(Pro)renin Revisited: New Insights from Studies in Mast Cells

Angiotensin synthesis at tissue sites is well-established, and interference with tissue angiotensin is now believed to underlie the beneficial effects of renin-angiotensin system blockers. At first it was thought that the renin required to synthesize angiotensin at tissue sites was also synthesized locally. Recent studies show, however, that this is not the case at important cardiovascular sites like the heart and vessel wall. Moreover, extrarenal sites that do express the renin gene release prorenin, the inactive precursor of renin, instead of renin. This chapter provides an update on the sources of (pro)renin in the body, lists the known stimulants and inhibitors of its production, and discusses the concept that prorenin rather than renin determines tissue angiotensin generation

The (pro)renin receptor. A decade of research: What have we learned?

The discovery of a (pro)renin receptor ((P)RR) in 2002 provided a long-sought explanation for tissue renin-angiotensin system (RAS) activity and a function for circulating prorenin, the inactive precursor of renin, in end-organ damage. Binding of renin and prorenin (referred to as (pro)renin) to the (P)RR increases angiotensin I formation and induces intracellular signalling, resulting in the production of profibrotic factors. However, the (pro)renin concentrations required for intracellular signalling in vitro are several orders of magnitude above (patho)physiological plasma levels. Moreover, the phenotype of prorenin-overexpressing animals could be completely attributed to angiotensin generation, possibly even without the need for a receptor. The efficacy of the only available putative (pro)renin receptor blocker handle region peptide remains doubtful, leading to inconclusive results. The fact that, in contrast to other RAS components, (P)RR knock-outs, even tissue-specific, are lethal, points to an important, (pro)renin-independent, function of the (P)RR. Indeed, recent research has highlighted ancillary functions of the (P)RR as an essential accessory protein of t

Prorenin anno 2008

For many years, prorenin has been considered to be nothing more than the inactive precursor of renin. Yet, its elevated levels in diabetic subjects with microvascular complications and its extrarenal production at various sites in the body suggest otherwise. This review discusses the origin, regulation, and enzymatic activity of prorenin, its role during renin inhibition, and the angiotensin-dependent and angiotensin-independent consequences of its binding to the recently discovered (pro)renin receptor. The review ends with the concept that prorenin rather than renin determines tissue angiotensin generation

Circulating versus tissue renin-angiotensin system: On the origin of (pro)renin

Angiotensin synthesis at tissue sites is well established, and interference with tissue angiotensin is now believed to underlie the beneficial effects of renin-angiotensin system blockers. initially, it was thought that the renin required to synthesize angiotensin at tissue sites was also synthesized locally. However, recent studies show this is not the case at important cardiovascular sites (eg, the heart and vessel wall). Moreover, extrarenal sites that express the renin gene release prorenin, the inactive precursor of renin, instead of renin. This review provides an update on the sources of (pro)renin in the body, lists the known stimulants and inhibitors of its production, and discusses the concept that prorenin rather than renin determines tissue angiotensin generation

Renin and prorenin disappearance in humans post-nephrectomy: evidence for binding?

To study the distribution of kidney-derived renin-angiotensin system (RAS) components in humans, we monitored the decline in plasma prorenin, renin, angiotensin (Ang) I and Ang II post-nephrectomy. Prorenin and renin decreased biphasically, prorenin displaying a slower elimination. The distribution half life was similar for both. Angiotensins followed the disappearance of renin. One-two days post-nephrectomy, stable plasma concentrations at 5-10% ( renin and angiotensins) and 25-30% (prorenin) of pre-nephrectomy levels were reached. The total amount of kidney-derived renin and prorenin in the body was approximate to 10 times as much as the amount in blood. Prorenin also originated at extrarenal sites. The renin levels in anephrics corresponded with the percentage of prorenin that in vitro has a so-called 'open conformation' (i.e., displays enzymatic activity), suggesting that renin in anephrics is in fact 'open' prorenin. Haemodialysis nor captopril significantly affected the level of any RAS component in anephrics. In conclusion, renal renin/prorenin enter tissue sites in humans, and renal renin is the main determinant of plasma angiotensins. Whether prorenin contributes to tissue angiotensin generation in humans remains to be determined