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(Hypertension. 2009;53:1062.)
© 2009 American Heart Association, Inc.

Original Articles

Chronic Increases in Circulating Prorenin Are not Associated With Renal or Cardiac Pathologies

Chantal Mercure; Gary Prescott; Marie-Josée Lacombe; David W. Silversides; Timothy L. Reudelhuber

From the Laboratory of Molecular Biochemistry of Hypertension, Clinical Research Institute of Montreal (C.M., G.P., M-J.L., T.L.R.); Department of Medicine, University of Montreal (T.L.R.), Montreal, Quebec, Canada; and Centre de Recherche en Reproduction Animale, Faculté de Médecine Vétérinaire de l’Université de Montréal (D.W.S.), St Hyacinthe, Québec, Canada.

Correspondence to Timothy L. Reudelhuber, IRCM, 110 Pine Ave West, Montreal, Quebec H2W 1R7, Canada. E-mail reudelt{at}ircm.qc.ca

Elevated levels of circulating prorenin, the precursor of renin, have been reported to precede the appearance of microvascular complications in diabetes mellitus. Although several studies using animal models have attempted to address the link between elevated prorenin and the tissue remodeling and damage associated with both hypertension and diabetes mellitus, the results have been contradictory, and the mechanism whereby prorenin might contribute to these pathologies remains a subject of debate. To directly test the role of prorenin in these pathologies, we generated transgenic mice with selective increases (13- to 66-fold) in circulating native or active site-mutated prorenin. Systolic blood pressure was either unchanged or increased (+25 mm Hg) in native prorenin-expressing mice, whereas the mice expressing active site-mutated prorenin showed no significant differences in systolic blood pressure compared with control animals. There was no increase in cardiac fibrosis or renal glomerular sclerosis in any of the transgenic animals tested, even at an advanced age (18 months). Captopril (an angiotensin-converting enzyme inhibitor) rapidly normalized blood pressure of hyperproreninemic mice, whereas infusion of the putative antagonist of the prorenin receptor (handle region peptide) had no effect. These results suggest that the primary consequence of chronic elevations in circulating prorenin is an increase in blood pressure and do not support a role for prorenin as the primary causative agent in cardiac fibrosis or renal glomerular injury. The lack of effect seen with active site-mutated prorenin and the efficacy of angiotensin-converting enzyme inhibition are also consistent with prorenin acting through the generation of angiotensin II to raise blood pressure.

Key Words: hypertension • renin-angiotensin system • prorenin • transgenic mice • renin • cardiac remodeling • glomerulosclerosis

This article has been cited by other articles:

				D. J. Campbell Method of Blood Collection May Explain the Suppression of Plasma Renin Concentration in Prorenin Transgenic Mice Hypertension, July 1, 2009; 54(1): e12 - e12. [Full Text] [PDF]

				T. L. Reudelhuber Response to Method of Blood Collection May Explain the Suppression of Plasma Renin Concentration in Prorenin Transgenic Mice Hypertension, July 1, 2009; 54(1): e13 - e13. [Full Text] [PDF]