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Activation of Plasma and Amniotic Prorenin by Metalloprotease and Trypsin^*

Departments of Pharmacology and Internal Medicine, University of Texas Health Science Center at Dallas Dallas, Texas 75235

Address requests for reprints to: Dr. Ervin G. Erdös, Departments of Anesthesiology and Pharmacology, University of Illinois College of Medicine at Chicago, 1740 West Taylor Street, Suite 3200 West, Box 6998, Chicago, Illinois 60680.

Human renin occurs in a latent form as prorenin in blood and amniotic fluid. We found that the metalloprotease thermolysin is a more potent activator of amniotic and plasma prorenin than trypsin, provided the thermolysin ₂-macroglobulin plasma inhibitor was inactivated. Thermolysin fully activated amniotic prorenin at a 23-fold lower molar concentration than trypsin, and renin activated by thermolysin was more stable 4han when activated by trypsin. Thermolysin also activated plasma prorenin at a 16-fold lower concentration than trypsin in the presence of methylamine (100 mM). Thermolysin activated prorenin directly, because added inhibitors of other endogenous proteases did not block the activation. The maximum activation values obtained after incubation with trypsin or thermolysin in plasma samples from 17 norrnotensive and 58 hypertensive subjects were similar. The mean renin concentration did not differ significantly in normotensives and hypertensives, but after activation, total renin was significantly higher in hypertensive subjects (89.8 v. 53.4 ng angiotensin I/h-ml). The K_m of the substrate, angiotensinogen, was about the same with both active renin and activated prorenin (281–290 nM). The mol wt of prorenin was 60,000 after gel filtration; activation by thermolysin reduced it to 51,000. Thus, thermolysin, which has a different peptide bond specificity than trypsin, is another model for a prorenin activator.

^* This work was supported in part by NIH Grants HL-16370 and HL-20594.

Received July 26, 1985.