Dose-dependent titration of prorenin and blood pressure in Cyp1a1ren-2 transgenic rats: absence of prorenin-induced glomerulosclerosis.
OBJECTIVE
Prorenin has been associated with cardiovascular disease and the development of glomerulosclerosis via a renin/prorenin receptor. In cyp1a1ren-2 transgenic rats, prorenin levels and arterial pressure can be increased by oral administration of indole-3-carbinol (I3C). The transgenic strain has been used as a model of malignant hypertension.


METHODS
The present study was designed to test the hypotheses that (i) low doses of I3C would result in dose-dependent sustained increases in arterial pressure without signs of malignancy, making cyp1a1ren-2 transgenic rats a useful model to study nonmalignant hypertension, and (ii) cyp1a1ren-2 transgenic rats would develop glomerulosclerosis when they were chronically exposed to 0.125% I3C in their diet.


RESULTS
I3C treatment for 2 weeks resulted in increases of plasma prorenin concentrations and arterial pressure in a dose-dependent manner. Rats thrived well over a period of 12 weeks on dietary I3C concentrations (wt/wt) of 0.125%. Plasma prorenin concentration rose from 0.1 +/- 0.1 microg to 17.9 +/- 5.0 mug angiotensin I/ml per h (P < 0.01) and mean arterial pressure increased to a plateau of 170 +/- 5 mmHg (P < 0.001) between weeks 6 and 12. After 12 weeks of 0.125% I3C, rats exhibited moderate hypertensive renal vasculopathy, but no histological signs of glomerulosclerosis.


CONCLUSIONS
The cyp1a1ren-2 transgenic rat model allows for chronic dose-dependent titration of arterial pressure by a simple and non-invasive intervention, making this strain a useful model to study malignant and nonmalignant arterial hypertension. High circulating prorenin levels per se do not cause glomerulosclerosis.
Peters
Barbara
B
Department of Cardiovascular Medicine, University of Greifswald, Greifswald, Germany. bspeters@gmx.de
Grisk
Olaf
O
Becher
Bertram
B
Wanka
Heike
H
Kuttler
Beate
B
Lüdemann
Jan
J
Lorenz
Gerd
G
Rettig
Rainer
R
Mullins
John J
JJ
Peters
Jörg
J
D000284:Administration, Oral; D000450:Aldosterone / Q000097:blood; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000187:drug effects*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005923:Glomerulosclerosis, Focal Segmental / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D007211:Indoles / Q000008:administration & dosage*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D012083:Renin / Q000097:blood* / Q000235:genetics; D013995:Time; D017186:Titrimetry
D007211:Indoles; C473112:Ren2 protein, mouse; D000450:Aldosterone; C016517:indole-3-carbinol; D019363:Cytochrome P-450 CYP1A1; D012083:Renin