(Pro)renin receptors: are they biologically relevant?

PURPOSE OF REVIEW: The recent introduction of a renin inhibitor, aliskiren, into the clinical arena has revived interest in renin and its precursor prorenin. In addition, a renin-binding and prorenin-binding receptor has been found, which not only activates prorenin but also induces angiotensin-independent signaling. This review addresses the question of whether this receptor has any biological relevance. RECENT FINDINGS: Prorenin is the preferred agonist of the (pro)renin receptor. When bound to the receptor, prorenin undergoes a conformational change allowing it to display full enzymatic activity. Receptor activation by renin/prorenin triggers the mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 signaling pathway, and human (pro)renin receptor transgenic rats develop glomerulosclerosis and hypertension in the absence of changes in renin or angiotensin. Aliskiren prevents angiotensin I generation by receptor-bound prorenin but does not block signaling. Conflicting results have been obtained with the putative (pro)renin receptor antagonist 'handle region peptide', suggesting that its efficacy depends on experimental conditions. SUMMARY: Although it is tempting to speculate that the (pro)renin receptor is the missing link providing a role for prorenin in tissue angiotensin generation, the discrepant results with handle region peptide and the lack of clinical studies with (pro)renin receptor blockers do not yet firmly support such a role.