HUMAN RENIN-DEPENDENT HYPERTENSION IN RATS TRANSGENIC FOR HUMAN ANGIOTENSINOGEN

To examine the utility of rats transgenic for human angiotensinogen in the study of human renin-induced hypertension, we first developed ass ays to measure both the human and rat renin-angiotensin systems in the se rats. We used human and mouse renin, transgenic human angiotensinog en, and the human renin inhibitor Ro 42-5892 to determine human- and r at-specific plasma angiotensinogen concentrations, renin activity, and renin concentration. The assays were validated with rat and human pla sma mixed in known amounts and with plasma from rats transgenic for hu man renin. We then tested the human angiotensinogen-transgenic rats by infusing recombinant human renin over 10 days (50 ng/h, n=4) with osm otic minipumps. High human angiotensinogen transgene expression was fo und in the liver, brain, kidney, gastrointestinal tract, and aorta, wh ereas rat angiotensinogen gene expression was detected in the liver an d brain. During human renin infusion, blood pressure increased to >200 /150 mm Hg. Before infusion, human angiotensinogen was 100-fold greate r than rat angiotensinogen (141+/-73 versus 1.2+/-0.16 mu g angiotensi n I/mL); the relation was not changed by renin infusion. Plasma renin activity increased 300-fold; human plasma renin concentration increase d to very high levels (449+/-262 ng of angiotensin I per mL per hour), whereas rat plasma renin concentration decreased to undetectable leve ls. Thus, chronic human renin infusion resulted in severe hypertension with extreme plasma renin activity and plasma renin concentration. Ho wever, even at these levels, human angiotensinogen was not rate limiti ng and angiotensin II was not a significant stimulus for angiotensinog en production. We conclude that these transgenic rats represent a nove l model of human renin-dependent hypertension.