Plasma prorenin in humans and dogs. Species differences and further evidence of a systemic activation cascade

We have studied the dog as a potential model for the human plasma prorenin-renin system. On a regular sodium intake, healthy conscious dogs apparently have a much lower plasma renin activity (PRA) than healthy human volunteers. Cryoactivation of prorenin is virtually absent in dogs, in contrast to that in humans, but becomes more effective after preacidification of the plasma. The concentration of trypsin required for optimal activation of prorenin is 6 to 10 times higher for dog plasma, revealing a prorenin:renin ratio about 10 times greater than in humans. Dialysis of posttryptic plasma decreases the PRA, but it remains 5 times higher than in pretryptic plasma, indicating that activation is not totally dependent on any renin system component that has been rendered dialyzable by trypsin, e.g., substrate converted to tetradecapeptide (TDP). This argues against the view that tryptic activation is attributable to angiotensin production from TDP by the action of cathepsin D, rather than from new renin converted from prorenin. The posttryptic increase in PRA is evident whether plasma incubation is carried out at pH 6.0 or at 7.4, and can be largely blocked by pepstatin, which also implicates a prorenin-renin mechanism rather than TDP-cathepsin. The low PRA in dogs, the negligible cryoactivation and its improvement by preacidification, and the requirement and tolerance of high trypsin concentrations, all point to greater protease inhibition in dog plasma and/or departures from the enzyme(s) responsible for human prorenin activation. Moreover, the tryptic activation of prorenin is not completed quickly as in human plasma, but carries over into the posttryptic stage of angiotensin generation, even in the presence of excess soybean trypsin inhibitor (SBTI), and other potent inhibitors. Such ongoing prorenin activation cannot be attributed only to trypsin itself, nor to kallikrein (both are inhibited by SBTI), but rather to some other enzyme(s) derived by the action of trypsin. This new prorenin convertase activity (possibly renin itself) can be effectively transferred from trypsinized to control dog plasma, in which it greatly accelerates prorenin activation. Thus, contrary to other reports, dog plasma has a high content of activatable prorenin, and with appropriate methodological changes, the dog can be used as an animal model for physiological and biochemical studies of the prorenin-renin system.