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首页> 外文期刊>American Journal of Physiology >Genetically increased angiotensin I-converting enzyme alters peripheral and renal vascular reactivity to angiotensin II and bradykinin in mice
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Genetically increased angiotensin I-converting enzyme alters peripheral and renal vascular reactivity to angiotensin II and bradykinin in mice

机译：遗传增加的血管紧张素I-转换酶改变对小鼠血管紧张素II和Bradykinin的外周和肾血管反应性

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摘要

Ajigiotensin I-converting enzyme (ACE) levels in humans are under strong genetic influence. Genetic variation in ACE has been linked to risk for and progression of cardiovascular and renal diseases. Causality has been documented in genetically modified mice, but the mechanisms underlying causality are not completely elucidated. To further document the vascular and renal consequences of a moderate genetic increase in ACE synthesis, we studied genetically modified mice carrying three copies of the ACE gene (three-copy mice) and littermate wild-type animals (two-copy mice). We investigated peripheral and renal vascular reactivity to angiotensin II and bradykinin in vivo by measuring blood pressure and renal blood flow after intravenous administration and also reactivity of isolated glomerular arterioles by following intracellular Ca~(2+) mobilization. Carrying three copies of the ACE gene potentiated the systemic and renal vascular responses to angiotensin II over the whole range of peptide concentration tested. Consistently, the response of isolated glomerular afferent arterioles to angiotensin II was enhanced in three-copy mice. In these mice, signaling pathways triggered by endothelial activation by bradykinin or carbachol in glomerular arterioles were also altered. Although the nitric oxide (NO) synthase (NOS)/NO pathway was not functional in arterioles of two-copy mice, in muscular efferent arterioles of three-copy mice NOS3 gene expression was induced and NO mediated the effect of bradykinin or carbachol. These data document new and unexpected vascular consequences of a genetic increase in ACE synthesis. Enhanced vasoconstrictor effect of angiotensin II may contribute to the risk for cardiovascular and renal diseases linked to genetically high ACE levels.
机译：人类中的嗜酸尼素I-转换酶（ACE）水平受到强烈的遗传影响。 ACE的遗传变异与心血管和肾病的风险有关。在基因改性小鼠中记录了因果关系，但潜在因果关系的机制并不完全阐明。为了进一步记录ACE合成中度遗传增加的血管和肾后果，我们研究了携带ACE基因（三拷贝小鼠）和凋落物野生型动物（两拷贝小鼠）的三拷贝的遗传修饰小鼠。通过测量静脉内给药后测量血压和肾血流，通过测量血压和肾血流，在体内调查外周血和肾血管反应性，并通过介于细胞内Ca〜（2+）动员中分离的肾小球动脉杆菌的反应性。携带三个ACE基因的副本将全身和肾脏血管反应加强对血管紧张素II的全系列肽浓度测试。始终如一地，在三拷贝小鼠中增强了分离的肾小球传入动脉对血管紧张素II的响应。在这些小鼠中，还改变了通过Bradykinin或肾小球动脉腺癌的内皮激活引发的信号通路。虽然一氧化氮（NO）合成酶（NOS）/ NO途径在双拷贝小鼠的动脉鎓中不起作用，但在肌肉出发的三拷贝小鼠的动作中，诱导了NOS3基因表达，并未介导Bradykinin或Carbachol的作用。这些数据记录了ACE合成遗传增加的新的和意外的血管后果。增强血管紧张素II的血管收缩效应可能导致与基因高王牌水平相关的心血管和肾病的风险。

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