Human prorenin

textabstractOur interest in inactive renin originates from the observation that plasma renin can be activated by several apparently unrelated modes of treatment. Dialysis of plasma against a pH 3.3 buffer at 0 C for 24 hours followed by another 24 hours of dialysis at neutral pH causes a five-fold increase in renin activity. Renin activity of plasma is also increased, albeit to a lesser extent, when plasma is stored at 0 C without prior acidification. Finally, the addition of trypsin and some other proteases, such as plasma kallikrein and plasmin, to plasma also increases renin activity. Theoretically, the increase in the enzymatic activity of renin could occur by several mechanisms: 1) changes of the fluid milieu of the enzyme, for instance changes in pH, certain metal ions, chaotropic agents, 2) reversible binding of an activator to the active site or to an allosteric site of the enzyme molecule, 3) destruction of an inhibitor of renin or dissociation of the inhibitor moiety from a renin-inhibitor complex, 4) alteration of the primary structure of inactive renin by limited proteolysis. The last possibility of activation by limited proteolysis is in agreement with the concept of a proenzyme-enzyme conversion. The existence of inactive forms of renin with a molecular weight greater than that of active renin has been demonstrated in plasma but the Mr-figures that have been reported are widely different. Such a concept is also in agreement with the presence of an additional nucleotide sequence in mouse submandibulary renin and human kidney renin e-DNA, which may correspond toN-terminal amino acid sequences that belong to the so-called prepropart of renin. Furthermore, there is recent evidence that the propart amino acid sequence of human kidney prorenin is also present in inactive renin of human plasma. Prorenin-renin conversion, within or outside the juxtaglomerular cells where prorenin is synthesized, could be an important regulatory step in the renin-angiotensin system. With this in mind we have studied some biochemical aspects of the activation of inactive renin and addressed the the possible physiological and clinical significance by measurements of inactive renin in plasma and other body fluids. This thesis describes our contributions to this subject in the past five year