Chronic increases in circulating prorenin are not associated with renal or cardiac pathologies.
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.
Mercure
Chantal
C
Department of Medicine, Laboratory of Molecular Biochemistry of Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada
Prescott
Gary
G
Lacombe
Marie-Josée
MJ
Silversides
David W
DW
Reudelhuber
Timothy L
TL
D000419:Albuminuria / Q000503:physiopathology; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002216:Captopril / Q000494:pharmacology; D004195:Disease Models, Animal; D006973:Hypertension / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D012313:RNA / Q000032:analysis; D011897:Random Allocation; D012016:Reference Values; D012083:Renin / Q000097:blood*; D012084:Renin-Angiotensin System / Q000502:physiology; D012680:Sensitivity and Specificity
D015415:Biomarkers; D012313:RNA; D002216:Captopril; D012083:Renin