Peters Barbara, Grisk Olaf, Becher Bertram, Wanka Heike, Kuttler Beate, Lüdemann Jan, Lorenz Gerd, Rettig Rainer, Mullins John J, Peters Jörg
Department of Cardiovascular Medicine, University of Greifswald, Greifswald, Germany.
J Hypertens. 2008 Jan;26(1):102-9. doi: 10.1097/HJH.0b013e3282f0ab66.
Prorenin has been associated with cardiovascular disease and the development of glomerulosclerosis via a renin/prorenin receptor. In cyp1a1ren-2 transgenic rats, prorenin levels and arterial pressure can be increased by oral administration of indole-3-carbinol (I3C). The transgenic strain has been used as a model of malignant hypertension.
The present study was designed to test the hypotheses that (i) low doses of I3C would result in dose-dependent sustained increases in arterial pressure without signs of malignancy, making cyp1a1ren-2 transgenic rats a useful model to study nonmalignant hypertension, and (ii) cyp1a1ren-2 transgenic rats would develop glomerulosclerosis when they were chronically exposed to 0.125% I3C in their diet.
I3C treatment for 2 weeks resulted in increases of plasma prorenin concentrations and arterial pressure in a dose-dependent manner. Rats thrived well over a period of 12 weeks on dietary I3C concentrations (wt/wt) of 0.125%. Plasma prorenin concentration rose from 0.1 +/- 0.1 microg to 17.9 +/- 5.0 mug angiotensin I/ml per h (P < 0.01) and mean arterial pressure increased to a plateau of 170 +/- 5 mmHg (P < 0.001) between weeks 6 and 12. After 12 weeks of 0.125% I3C, rats exhibited moderate hypertensive renal vasculopathy, but no histological signs of glomerulosclerosis.
The cyp1a1ren-2 transgenic rat model allows for chronic dose-dependent titration of arterial pressure by a simple and non-invasive intervention, making this strain a useful model to study malignant and nonmalignant arterial hypertension. High circulating prorenin levels per se do not cause glomerulosclerosis.
通过肾素/前肾素受体，前肾素与心血管疾病及肾小球硬化的发生相关。在cyp1a1ren - 2转基因大鼠中，口服吲哚 - 3 - 甲醇（I3C）可使前肾素水平和动脉血压升高。该转基因品系已被用作恶性高血压模型。
本研究旨在验证以下假设：（i）低剂量I3C会导致动脉血压呈剂量依赖性持续升高且无恶性征象，使cyp1a1ren - 2转基因大鼠成为研究非恶性高血压的有用模型；（ii）cyp1a1ren - 2转基因大鼠在饮食中长期暴露于0.125% I3C时会发生肾小球硬化。
I3C治疗2周导致血浆前肾素浓度和动脉血压呈剂量依赖性升高。大鼠在12周内以0.125%（重量/重量）的饮食I3C浓度生长良好。血浆前肾素浓度从0.1±0.1微克/小时升至17.9±5.0微克血管紧张素I/毫升（P < 0.01），平均动脉血压在第6至12周升至170±5 mmHg的平台期（P < 0.001）。在0.125% I3C处理12周后，大鼠表现出中度高血压性肾血管病变，但无肾小球硬化的组织学征象。
cyp1a1ren - 2转基因大鼠模型通过简单且非侵入性的干预实现动脉血压的慢性剂量依赖性滴定，使该品系成为研究恶性和非恶性动脉高血压的有用模型。高循环前肾素水平本身不会导致肾小球硬化。
