Prorenin is the enzymatically inactive precursor of renin. Recent interest has focused on the nonproteolytic activation of prorenin by antibodies and renin/prorenin receptors since markedly increased levels of circulating prorenin have been associated with both physiological and pathological changes. Prorenin has been considered to be activated in vivo proteolytically and/or non-proteolytically. It has been demonstrated in vitro the "gate" and "handle" regions in the prorenin molecule is crucial for its non-proteolytic activation by a protein-protein interaction. Prorenin was also activated by the renin/prorenin receptors. Decapeptides (10P-19P) known as "decoy" peptide and pentapeptides (11P-15P) named as "handle" region peptide, were observed to inhibit the binding of both prorenins to receptors. The "handle" region plays an important role in prorenin binding to the receptor and its enzymatic activity by non-proteolytic activation. Prorenin receptors so far revealed by animal experiments have indicated that the decoy peptide prevented diabetes nephropathy and retinopathy. It was postulated the existence of novel regulative system that stimulated signal transduction as well as that of renin-angiotensin system. These findings help to find out the clue to design useful drug with greater benefit on the end-organ damage in diabetes and hypertension than those of conventional renin-angiotensin system inhibitors.