(Pro)renin receptors: are they biologically relevant?

Abstract

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. 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. 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.