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(Circulation Research. 1999;84:1067-1072.)
© 1999 American Heart Association, Inc.

Original Contributions

In Vivo Enzymatic Assay Reveals Catalytic Activity of the Human Renin Precursor in Tissues

Danielle Methot, David W. Silversides, Timothy L. Reudelhuber

From the Laboratory of Molecular Biochemistry of Hypertension and Medical Research Canada Multidisciplinary Research Group on Hypertension (D.M., T.L.R.), Clinical Research Institute of Montreal, Montreal, and Centre de recherche en reproduction animal (D.W.S.), Faculty of Veterinary Medicine, University of Montreal, St-Hyacinthe, Quebec, Canada.

Correspondence to Timothy L. Reudelhuber, Laboratory of Molecular Biochemistry of Hypertension, Clinical Research Institute of Montreal, 110 Pine Ave West, Montreal, Quebec, H2W 1R7, Canada. E-mail reudelt{at}ircm.qc.ca

Abstract—The aspartyl protease renin is secreted into the circulation of mammals in 2 forms: the proteolytically processed active form of the enzyme and the precursor form, prorenin. Prorenin has no detectable enzymatic activity in the circulation, but it is the exclusive form of the enzyme produced by several tissues that also produce the other components of the renin enzymatic cascade (renin-angiotensin system). To test whether prorenin might be enzymatically active in these tissues, transgenic mice expressing the human renin substrate (angiotensinogen) exclusively in the pituitary gland were mated to mice expressing either active human renin or prorenin in the same tissue. Measurement of in vivo product formation in pituitary glands of double-transgenic mice revealed that human prorenin was enzymatically active, and Western blot analysis demonstrated that this prorenin was in the precursor form with its prosegment attached. This in vivo enzymatic assay demonstrates for the first time that human prorenin can be activated within tissues by nonproteolytic means, where it could contribute to the activity of a localized renin-angiotensin system.

Key Words: renin • prorenin • angiotensin

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