Short-Lived Active Prorenin: Precursor of So-Called Native Prorenin

Abstract

The enzymatic activity of the aspartic protease, renin, is critical for its function in blood pressure regulation and sodium homeostasis. Incubation of so-called native prorenin at low pH leads to its activation. After binding to transition-state mimicking renin inhibitors at neutral pH, prorenin attains the active conformation, as indicated by immunosorbent assay using monoclonal antibodies specific for epitopes of the prosegment or the renin body. A comparison of immunosorbent assay with enzyme-kinetic assay revealed the intermediary steps of prorenin auto-activation/inactivation. The kinetically identified intermediary steps of activation/inactivation correspond with the published crystal structures of free renin, free prorenin, and renin in complex with inhibitors. Both renin and activated prorenin exist in 2 forms, α and β. The α form is active, and the α/β quantity ratio is 2.5. The kidney produces renin and prorenin, while the ovarium, placenta, and eye produce inactive prorenin. The production of renin by these organs has never been demonstrated. We propose that the so-called native prorenin in extracellular fluid, including the circulation, is derived, at least partly, from short-lived active prorenin. Its potential paracrine function is discussed.