Blood pressure-independent effects in rats with human renin and angiotensinogen genes.
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 approximately 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.
Mervaala
E
E
Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin, Germany.
Müller
D N
DN
Schmidt
F
F
Park
J K
JK
Gross
V
V
Bader
M
M
Breu
V
V
Ganten
D
D
Haller
H
H
Luft
F C
FC
D000419:Albuminuria / Q000503:physiopathology / Q000517:prevention & control; D000804:Angiotensin II / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D000808:Angiotensinogen / Q000235:genetics / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006332:Cardiomegaly / Q000503:physiopathology / Q000517:prevention & control; D004231:Diuresis; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D006852:Hydrochlorothiazide / Q000494:pharmacology; D019394:Ki-67 Antigen / Q000032:analysis; D007668:Kidney / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000737:chemistry; D009318:Natriuresis; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D012083:Renin / Q000097:blood / Q000235:genetics / Q000502:physiology*; D012110:Reserpine / Q000494:pharmacology; D012964:Sodium / Q000652:urine; D019076:Transgenes / Q000235:genetics / Q000502:physiology
D000959:Antihypertensive Agents; D019394:Ki-67 Antigen; D011480:Protease Inhibitors; D006852:Hydrochlorothiazide; D000808:Angiotensinogen; D000804:Angiotensin II; D006830:Hydralazine; D012110:Reserpine; D012964:Sodium; D012083:Renin