Cardiovascular phenotype of mice lacking all three subtypes of angiotensin II receptors
Cardiovascular phenotype of mice lacking all three subtypes of angiotensin II receptors
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DOI：
10.1096/fj.08-108316
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发表时间：
2008-08-01
期刊：
影响因子：
4.8
通讯作者：
Walther, Thomas
中科院分区：
文献类型：
--
作者：
Gembardt, Florian;Heringer-Walther, Silvia;Walther, Thomas
血管紧张素II激活两种不同的受体，血管紧张素II受体1型（AT1）和2型（AT2）。在啮齿动物中，鉴定出两种AT1亚型（AT1a和AT1b）。为了确定受体特异性功能和血管紧张素II可能独立于其三种已知受体的作用，我们产生了血管紧张素II受体缺乏的小鼠，其中一种缺乏，两种缺乏，或者三种都缺乏（三重敲除）。三次击倒是至关重要和多产的，但生存受到损害。三基因敲除小鼠的低血压和肾脏组织学异常与缺乏两种AT1亚型的小鼠相当。所有缺乏AT1a的组合都以降低心率为特征。AT1a缺失会损害血管紧张素II大剂量注射的体内加压反应，而AT1b和/或AT2缺失则没有影响。然而，at1a缺陷小鼠中AT1b的额外缺乏进一步损害了血管紧张素II的血管收缩能力。虽然血管收缩剂的一般特性没有改变，但血管紧张素II在三重敲除中未能改变血压，这表明没有其他受体直接参与血管紧张素II的升压作用。我们的数据表明，缺乏所有三种血管紧张素II受体的小鼠是更好地了解肾素-血管紧张素系统结构和功能以及寻找独立于AT1和AT2的血管紧张素II效应的理想工具。
Angiotensin II activates two distinct receptors, the angiotensin II receptors type 1 (AT1) and type 2 (AT2). In rodents, two AT1 subtypes were identified (AT1a and AT1b). To determine receptor-specific functions and possible angiotensin II effects independent of its three known receptors we generated mice deficient in either one of the angiotensin II receptors, in two, or in all three (triple knockouts). Triple knockouts were vital and fertile, but survival was impaired. Hypotension and renal histological abnormalities in triple knockouts were comparable to those in mice lacking both AT1 subtypes. All combinations lacking AT1a were distinguished by reduced heart rate. AT1a deletion impaired the in vivo pressor response to angiotensin II bolus injection, whereas deficiency for AT1b and/or AT2 had no effect. However, the additional lack of AT1b in AT1a-deficient mice further impaired the vasoconstrictive capacity of angiotensin II. Although general vasoconstrictor properties were not changed, angiotensin II failed to alter blood pressure in triple knockouts, indicating that there are no other receptors involved in direct angiotensin II pressor effects. Our data identify mice deficient in all three angiotensin II receptors as an ideal tool to better understand the structure and function of the renin-angiotensin system and to search for angiotensin II effects independent of AT1 and AT2.