LAUSR

Since the initial discovery of a pressor activity in kidney homogenates to its isolation and identification almost 100 years later, the protease renin constitutes a critical step in the activation of the reninangiotensin system (RAS) cascade leading to the generation of Ang II (angiotensin II) and stimulation of the ACE (angiotensin-converting enzyme)–Ang II–AT1R (AT1 receptor) axis. Renin is synthesized initially as a proenzyme (prorenin) in which the N-terminal region occupies the active site of the enzyme to maintain an inactive state. Processing of prorenin occurs in secretory vesicles within renal juxtaglomerular cells by an unidentified protease that cleaves the proenzyme to generate active renin. The juxtaglomerular cells release both prorenin and renin in essentially a fixed ratio as prorenin does not undergo additional proteolytic processing to its active form in the blood. Circulating levels of prorenin generally exceed that of renin and the levels may further increase under various conditions including pregnancy and diabetes. Nguyen et al1 identified a key piece of the prorenin puzzle by demonstrating a cellular protein, termed the PRR (prorenin receptor) that binds prorenin and renin or (pro)renin at low nanomolar (nM) affinity. Binding of prorenin to the PRR induces a conformational change that fully activates the protease. Importantly, the PRR does not cleave prorenin and the disassociation of prorenin from PRR would revert the enzyme to its original inactive state.