Blood pressure-independent effects in rats with human renin and angiotensinogen genes

The blood pressure-independent effects of angiotensin LT (Ang II) were exam ined in double transgenic rats (dTGR) harboring human renin and human angio tensinogen genes, in which the end-organ damage is due to the human compone nts of the renin angiotensin system. Triple-drug therapy (hydralazine 80 mg /L, reserpine 5 mg/L, and hydrochlorothiazide 25 mg/L in drinking water) wa s started immediately after weaning. Triple-drug therapy normalized blood p ressure and coronary resistance, only partially prevented cardiac hypertrop hy, and had no effect on ratio of renal weight to body weight. Although tri ple-drug therapy delayed the onset of renal damage, severe albuminuria neve rtheless occurred. Semiquantitative scoring of ED-1-positive and MIB-5-posi tive (nuclear cell proliferation-associated antigen Ki-67) cells showed pro found perivascular monocyte/macrophage infiltration and cell proliferation in kidneys and hearts of untreated dTGR. Triple-drug therapy had only a min imal 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 ef fects of HRI were at least in part due to improved renal hemodynamics and d istal tubular function, since HRI shifted renal pressure-diuresis/natriures is curves leftward by approximate to 35 mm Hg, increased glomerular filtrat ion rate and renal blood flow, and shifted the fractional water and sodium excretion curves leftward. In untreated dTGR, plasma Ang II was increased b y 400% and renal Ang II level was increased by 300% compared with Sprague-D awley rats. HRI decreased plasma human renin activity by 95% and normalized Ang Il levels in both plasma and kidney compared with triple-drug therapy. Our findings indicate that in dTGR harboring human renin and angiotensinog en genes, Ang II causes end-organ damage and promotes inflammatory response and cellular growth largely independent of blood pressure.