(Hypertension. 2000;35:587.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Blood Pressure–Independent Effects in Rats With Human Renin and Angiotensinogen Genes
From the Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin (Germany) (E.M., D.N.M., F.S., J-K.P., V.G., H.H., F.C.L.); Institute of Biomedicine, University of Helsinki (Finland) (E.M); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B., D.G., H.H., F.C.L.); dF. Hoffmann–La Roche, Basel, Switzerland (V.B.); and Institute for Clinical Pharmacology, Universitätsklinikum-Benjamin Franklin, Free University of Berlin (Germany) (D.G.).
Correspondence to Friedrich C. Luft, Franz Volhard Clinic, Wiltberg Strasse 50, 13125 Berlin, Germany. E-mail luft{at}fvk-berlin.d
Abstract—The blood
pressure–independent effects of angiotensin II (Ang II)
were examined in double transgenic rats (dTGR) harboring human renin
and human angiotensinogen genes, in which the end-organ
damage is due to the human components of the renin
angiotensin system. Triple-drug therapy
(hydralazine 80 mg/L, reserpine 5 mg/L, and
hydrochlorothiazide 25 mg/L in drinking water) was
started immediately after weaning. Triple-drug therapy normalized blood
pressure and coronary resistance, only partially prevented
cardiac hypertrophy, and had no effect on ratio of renal
weight to body weight. Although triple-drug therapy delayed the onset
of renal damage, severe albuminuria nevertheless occurred.
Semiquantitative scoring of ED-1–positive and MIB-5–positive (nuclear
cell proliferation–associated antigen Ki-67) cells showed profound
perivascular monocyte/macrophage infiltration and cell
proliferation in kidneys and hearts of untreated dTGR. Triple-drug
therapy had only a minimal effect on local inflammatory response or
vascular cell proliferation. In contrast, a novel orally active human
renin inhibitor (HRI), 30 mg/kg by gavage for 4 weeks,
normalized blood pressure and coronary resistance and also
prevented cardiac hypertrophy and albuminuria.
ED-1–positive cells and MIB-5–positive cells were decreased by HRI in
hearts and kidneys almost to levels observed in normotensive
Sprague-Dawley rats. The renoprotective effects of HRI were at least in
part due to improved renal hemodynamics and distal
tubular function, since HRI shifted renal
pressure-diuresis/natriuresis curves leftward by 
35
mm Hg, increased glomerular filtration rate and
renal blood flow, and shifted the fractional water and sodium excretion
curves leftward. In untreated dTGR, plasma Ang II was increased by
400% and renal Ang II level was increased by 300% compared with
Sprague-Dawley rats. HRI decreased plasma human renin activity by 95%
and normalized Ang II levels in both plasma and kidney compared with
triple-drug therapy. Our findings indicate that in dTGR harboring human
renin and angiotensinogen genes, Ang II causes end-organ
damage and promotes inflammatory response and cellular growth largely
independent of blood pressure.
Key Words: renin • angiotensinogen • angiotensin II • albuminuria • cell proliferation • natriuresis
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