Biochemical properties of renin and prorenin binding to the (pro)renin receptor

Abstract

The discovery of (pro)renin receptor, (P)RR, has made the renin-angiotensin system (RAS) more multifaceted. Interaction of renin and prorenin with this receptor has set a new perspective about the physiological functions, activation mechanism and pathophysiological roles of renin/prorenin. Uses of peptides mimicking the structure of the ligands have been very effective for determining structure-function relationship between the ligands and receptor. The probable pivotal role of decoy peptide region (R 10P IFLKRMPSI 19P ) of prorenin prosegment was suggested for higher binding affinity of prorenin to (P)RR than that of mature renin. Recently, 'hinge' region peptide (S 149 QGVLKEDVF 158 ) in renin/prorenin molecule has been reported. Both renin and prorenin can interact with (P)RR through the 'hinge' region. Furthermore, it has been proposed that prorenin has multiple binding sites whereas renin has a single binding site for (P)RR. To comprehend the activation mechanism of renin and prorenin after receptor binding, it is very important to understand their interaction with the receptor. Several kinds of peptides designed from the regions of the tertiary structure of renin and predicted model of prorenin facilitated the study of the in vitro binding mechanisms for renin and prorenin to (P)RR. Here, a series of recent in vitro studies was reviewed to discuss a possible binding mechanism of renin/prorenin to the (P)RR.

Renin- and Prorenin-Induced Effects in Rat Vascular Smooth Muscle Cells Overexpressing the Human (Pro)Renin Receptor

“…1,15,16 When comparing renin and prorenin in the same assay, most studies revealed that the dissociation constant of prorenin for the human (P)RR is 3-to 4-fold lower than that of renin. Nanomolar dissociation constants are difficult to reconcile with the picomolar levels of renin (Ϸ0.5 pmol/L) and prorenin (Ϸ5.0 pmol/L) in extracellular fluid 17 but explain why, in most in vitro studies, investigating (pro)renin-(P)RR interaction high nanomolar (Յ100 nmol/L) 10 (pro)renin concentrations were required to observe effects.…”

“…It has even been claimed that HRP also prevents renin binding to the (P)RR, acts as an agonist of the (P)RR, and/or has (P)RR-independent effects. 16,21,22 To obtain a better understanding of the apparent discrepancy between the in vitro and in vivo consequences of (pro)renin-(P)RR interaction, we carefully compared the concentration dependency of the effects of human renin and prorenin via the human (P)RR (h[P]RR) in aortic vascular smooth muscle cells (VSMCs) obtained from rats overexpressing the h(P)RR in VSMCs and their wild-type controls. 3 We focused on Ang II formation and signaling, making use of putative blockers of the (P)RR (human and rat HRP) and V-ATPase (bafilomycin), in addition to knocking down the (P)RR with small interfering (si) RNA.…”

Human Prorenin Structure Sheds Light on a Novel Mechanism of Its Autoinhibition and on Its Non-Proteolytic Activation by the (Pro)renin Receptor

“…Among others, it binds both renin [K d (rat) = 20.0 nM; K d (human) = 4.5 nM] and prorenin [K d (rat) = 8.0 nM; K d (human) = 1.0 nM] (data at 4°C). [6][7][8] Accordingly, the (P)RR has been initially characterized as a component of the renin-angiotensin system. It was suggested that it triggers the activation of prorenin through a conformational change.…”

Analysis of Oxidative Stress Markers Malondialdehyde, Glutathione, Nitric Oxide, and Prorenin Level in Preeclampsia Placental Tissues

“…Prorenin is an inactive precursor of renin and has concentration 10 times higher than renin. Prorenin activation mechanism to be renin needs proteolytic cleavage by protease, and also by a non-proteolytic mechanism through regulation of pH and temperature [21].…”