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

Abstract

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 the vacuolar-type H(+)-ATPase (V-ATPase), and in this role, it acts as an intermediate in Wnt signalling independent of (pro)renin. In conclusion, (pro)renin-dependent signalling is unlikely in non-(pro)renin synthesizing organs, and the (P)RR role in V-ATPase integrity and Wnt signalling may explain some, if not all of the phenotypes previously associated with (pro)renin-(P)RR interaction.

Fig. 1

Predicted domain structure and proteolytic fragments of the (P)RR. A putative furin cleavage site is indicated by an asterisk. Abbreviations: SP, signal peptide; TM, transmembrane domain

Fig. 2

Functions of the (P)RR in (pro)renin activation and signalling (left), Wnt signalling (middle), and V-ATPase integrity in autophagic digestion (right). See text for explanation. Abbreviations used: ACE, angiotensin-converting enzyme; Ang, angiotensin; Aog, angiotensinogen; COX-2, cyclooxygenase-2; EGFR, epidermal growth factor receptor; Erk1/2, extracellular signal-regulated kinase 1/2; Fz/LRP6, frizzled/low-density lipoprotein receptor-related protein 6; PAI-1, plasminogen-activator inhibitor-1; PI3K, phosphoinositide 3-kinase; PLZF, promyelocytic leukemia zinc finger protein; (P)RR, (pro)renin receptor; TCF/LEF, T cell factor/lymphocyte enhancer-binding factor; TGF-β1, transforming growth factor-β1

Fig. 3

Prorenin detection with different assays. Until recently, measuring prorenin immunologically could only be done using a renin-specific immunoradiometric assay (IRMA). This kit makes use of an antibody recognizing the active site, and therefore, to allow prorenin detection, it first has to be converted to renin by cleaving off the prosegment, e.g., with trypsin. Alternatively, a renin inhibitor can interfere with the equilibrium that exists between ‘closed’ (inactive) and ‘open’ (active) prorenin. Normally, >98 % of prorenin is in the closed conformation. Yet, in the presence of a renin inhibitor, the equilibrium will shift into the direction of the open conformation [5, 26], i.e., exposing the active site, while the prosegment is still attached. Indeed, treatment for 48 h at 4 °C with the renin inhibitor aliskiren (10 μmol/L) [5] fully converts all prorenin molecules to the open conformation, allowing their detection in a renin-specific assay. This approach, as well as the proteolytic approach (cleaving off the prosegment), requires renin to be measured before and after treatment in order to determine the amount of prorenin from the difference between the two measurements. Recently, a new prorenin specific ELISA has been developed, making use of an antibody directed against the prosegment [58], allowing direct prorenin measurement without pretreatment. The method is fast, and the results are very consistent with those obtained with the renin IRMA measurements