Bohlender J, Ménard J, Wagner J, Luft F C, Ganten D
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Hypertension. 1996 Mar;27(3 Pt 2):535-40. doi: 10.1161/01.hyp.27.3.535.
To examine the utility of rats transgenic for human angiotensinogen in the study of human renin-induced hypertension, we first developed assays to measure both the human and rat renin-angiotensin systems in these rats. We used human and mouse renin, transgenic human angiotensinogen, and the human renin inhibitor Ro 42-5892 to determine human- and rat-specific plasma angiotensinogen concentrations, renin activity, and renin concentration. The assays were validated with rat and human plasma mixed in known amounts and with plasma from rats transgenic for human renin. We then tested the human angiotensinogen-transgenic rats by infusing recombinant human renin over 10 days (50 ng/h, n=4) with osmotic minipumps. High human angiotensinogen transgene expression was found in the liver, brain, kidney, gastrointestinal tract, and aorta, whereas rat angiotensinogen gene expression was detected in the liver and brain. During human renin infusion, blood pressure increased to >200/150 mm Hg. Before infusion, human angiotensinogen was 100-fold greater than rat angiotensinogen (141 +/- 73 versus 1.2 +/- 0.16 microg angiotensin l/mL); the relation was not changed by renin infusion. Plasma renin activity increased 300-fold; human plasma renin concentration increased to very high levels (449 +/- 262 ng of angiotensin I per mL per hour), whereas rat plasma renin concentration decreased to undetectable levels. Thus, chronic human renin infusion resulted in severe hypertension with extreme plasma renin activity and plasma renin concentration. However, even at these levels, human angiotensinogen was not rate limiting and angiotensin II was not a significant stimulus for angiotensinogen production. We conclude that these transgenic rats represent a novel model of human renin-dependent hypertension.
为了研究人血管紧张素原转基因大鼠在人肾素诱导的高血压研究中的效用，我们首先开发了检测方法来测定这些大鼠体内的人及大鼠肾素 - 血管紧张素系统。我们使用人及小鼠肾素、转基因人血管紧张素原和人肾素抑制剂Ro 42 - 5892来测定人及大鼠特异性血浆血管紧张素原浓度、肾素活性和肾素浓度。这些检测方法通过将已知量的大鼠和人血浆混合以及用人肾素转基因大鼠的血浆进行了验证。然后，我们通过用渗透微型泵在10天内输注重组人肾素（50 ng/h，n = 4）来测试人血管紧张素原转基因大鼠。在肝脏、脑、肾、胃肠道和主动脉中发现了高表达的人血管紧张素原转基因，而在肝脏和脑中检测到了大鼠血管紧张素原基因表达。在输注人肾素期间，血压升高至>200/150 mmHg。输注前，人血管紧张素原比大鼠血管紧张素原高100倍（141±73对1.2±0.16 μg血管紧张素I/mL）；肾素输注并未改变这种关系。血浆肾素活性增加了300倍；人血浆肾素浓度增加到非常高的水平（每毫升每小时449±262 ng血管紧张素I），而大鼠血浆肾素浓度降低到无法检测的水平。因此，慢性输注人肾素导致了严重高血压，伴有极高的血浆肾素活性和血浆肾素浓度。然而，即使在这些水平下，人血管紧张素原也不是限速因素，血管紧张素II也不是血管紧张素原产生的重要刺激因素。我们得出结论，这些转基因大鼠代表了一种新型的人肾素依赖性高血压模型。
