Enhanced Urinary Angiotensinogen Excretion in Cyp1a1-Ren2 Transgenic Rats With Inducible ANG II-Dependent Malignant Hypertension

Introduction: Previous studies have demonstrated that the urinary excretion of angiotensinogen is significantly increased in ANG II-infused hypertensive rats, which is associated with an augmentation of intrarenal ANG II levels. These findings suggest that urinary angiotensinogen excretion rates provide an index of intrarenal ANG II levels in ANG II-dependent hypertensive states. However, little information is available regarding the urinary excretion of angiotensinogen in ANG II-dependent malignant hypertension. Methods: This study was performed to determine if urinary angiotensinogen excretion is increased in Cyp1a1-Ren2 transgenic rats [strain name: TGR(Cyp1aRen2)] with inducible ANG II-dependent malignant hypertension. Adult male Cyp1a1-Ren2 rats (n = 6) were fed a normal diet containing 0.3% indole-3-carbinol (I3C) for 10 days to induce ANG II-dependent malignant hypertension. Results: Rats induced with I3C exhibited pronounced increases in systolic blood pressure (208 +/- 7 versus 127 +/- 3 mmHg; P < 0.001), marked proteinuria (29.4 +/- 3.6 versus 5.9 +/- 0.3 mg/d; P < 0.001) and augmented urinary angiotensinogen excretion (996 +/- 186 versus 241 +/- 31 ng/d; P < 0.01). Chronic administration of the AT 1 receptor antagonist, candesartan (25 mg/L in drinking water, n = 6), prevented the I3C-induced increases in systolic blood pressure (125 +/- 5 mmHg; P < 0.001), proteinuria (7.3 +/- 1.0 mg/d; P < 0.001) and urinary angiotensinogen excretion (488 +/- 51 ng/d, P < 0.01). Conclusions: These data demonstrate that the urinary excretion of angiotensinogen is markedly augmented in ANG II-dependent malignant hypertension. Such increased urinary angiotensinogen excretion may contribute to augmented intrarenal ANG II levels and, thereby, to the increased blood pressure in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension.