High human renin hypertension in transgenic rats
High human renin hypertension in transgenic rats
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DOI：
10.1161/01.hyp.29.1.428
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发表时间：
1997-01-01
期刊：
影响因子：
8.3
通讯作者：
Ganten, D
中科院分区：
文献类型：
--
作者：
Bohlender, J;Fukamizu, A;Ganten, D
我们开发了一个模型，自发性高的人肾素高血压的大鼠通过生产两个转基因株，一个人血管紧张素原与内源性启动子和人肾素与内源性启动子。两种转基因株均不高血压。然后将这些菌株杂交，产生双转基因菌株。雄性和雌性的双转基因大鼠均出现严重的高血压（平均收缩压，200 mm Hg），如果不治疗，平均55天后死亡。大鼠的人血浆肾素浓度为269 +/- 381（+/- SD）ng血管紧张素I（Ang I）/mL/小时，血浆肾素活性为177 +/- 176 ng Ang I/mL/小时，大鼠血管紧张素原浓度为1.49 +/- 1 μ g Ang I/mL，人血管紧张素原浓度为78 +/- 39 μ g Ang I/mL（n = 49）。对照组大鼠的血浆肾素活性为3.7 +/- 3.9 ng Ang I/mL/h，大鼠血管紧张素原为1.32 +/- 0.16 μ g Ang I/mL。通过RNA酶保护试验检测的血管紧张素原转基因表达普遍存在，但在肝脏中最突出。肾组织中肾素转基因表达较高，但肝组织中无。大鼠的特征是严重的心脏肥大，心肌细胞横截面增加，但心肌纤维化很少。肾脏显示肾小管萎缩、血管壁增厚和肾小管上皮细胞增多。血管紧张素转换酶抑制剂赖诺普利和特定的人肾素抑制剂雷米吉仑都能将血压降低到正常值。双转基因小鼠已经开发出来，表现出与这里描述的非常相似的特征;它们的基因表达相似。啮齿动物和人的肾素的特异性也有类似的记录。虽然现在可以在小鼠中进行许多优雅的生理学研究，但大鼠仍然提供了灵活性，特别是在详细的心脏和肾脏生理学和药理学方面。我们的结论是，这种双转基因菌株将有利于同时调查的遗传和病理生理方面的肾素诱导的高血压。可以在大鼠中研究人肾素的事实是该模型的独特特征。
We developed a model of spontaneously high human renin hypertension in the rat by producing two transgenic strains, one for human angiotensinogen with the endogenous promoter and one for human renin with the endogenous promoter. Neither transgenic strain was hypertensive. These strains were then crossed, producing a double transgenic strain. The double transgenic rats, both males and females, developed severe hypertension (mean systolic pressure, 200 mm Hg) and died after a mean of 55 days if untreated. The rats had a human plasma renin concentration of 269 +/- 381 (+/- SD) ng angiotensin I (Ang I)/mL per hour, plasma renin activity of 177 +/- 176 ng Ang I/mL per hour, rat angiotensinogen concentration of 1.49 +/- 1 mu g Ang I/mL, and human angiotensinogen concentration of 78 +/- 39 mu g Ang I/mL (n = 49). Control rats had plasma renin activity of 3.7 +/- 3.9 ng Ang I/mL per hour and rat angiotensinogen of 1.32 +/- 0.16 mu g Ang I/mL. Angiotensinogen transgene expression by RNase protection assay was ubiquitously present but most prominent in liver. Renin transgene expression was high in kidney but absent in liver. The rats featured severe cardiac hypertrophy, with increased cross section of cardiomyocytes but little myocardial fibrosis. The kidneys showed atrophic tubules, thickened vessel walls, and increased interstitium. Both the angiotensin-converting enzyme inhibitor lisinopril and the specific human renin inhibitor remikiren lowered blood pressure to normal values. Double transgenic mice have been developed that exhibit features quite similar to those described here; their gene expressions are similar. The specificity of rodent and human renin is similarly documented. Although many elegant physiological studies can now be done in mice, rats nevertheless offer flexibility, particularly in terms of detailed cardiac and renal physiology and pharmacology. We conclude that this double transgenic strain will facilitate simultaneous investigation of genetic and pathophysiological aspects of renin-induced hypertension. The fact that human renin can be studied in the rat is a unique feature of this model.