AbdAlla Said, Abdel-Baset Ahmed, Lother Heinz, el Massiery Adel, Quitterer Ursula
Heinrich-Pette-Institut, D-20251 Hamburg, Germany.
J Mol Neurosci. 2005;26(2-3):185-92. doi: 10.1385/JMN:26:2-3:185.
Angiotensin II plays a central role in the pathogenesis of hypertension and of related cardiovascular disorders by binding to and activating angiotensin II receptors (AT1 receptors). Sensitization to the vasopressor response of angiotensin II is a key feature in many cardiovascular disorders. However, underlying mechanisms responsible for angiotensin II hypersensitivity are barely understood. Because angiotensin II responsiveness of AT1 receptors can be specifically modified by AT1/B2 receptor dimerization, we determined the AT1 receptor dimerization status in an experimental model of hypertension. AT1/B2 receptor heterodimers were abundant on renal mesangial cells isolated from spontaneously hypertensive rats compared with that on cells from normotensive controls. Heterodimerization of AT1 with B2 receptors was correlated with high levels of B2 receptor protein on kidneys and on mesangial cells of hypertensive rats, as determined in immunoblot with receptor-specific antibodies. Specific inhibition of AT1/B2 receptor heterodimers revealed that these receptor heterodimers mediated an enhanced angiotensin II-stimulated Galphaq/11 activation and an increased endothelin-1 secretion of mesangial cells from hypertensive rats. Thus, AT1/B2 receptor heterodimerization contributes to angiotensin II hyperresponsiveness of mesangial cells in experimental hypertension.
血管紧张素II通过与血管紧张素II受体（AT1受体）结合并激活该受体，在高血压及相关心血管疾病的发病机制中发挥核心作用。对血管紧张素II的升压反应敏感是许多心血管疾病的一个关键特征。然而，导致血管紧张素II超敏反应的潜在机制却几乎不为人知。由于AT1受体与B2受体二聚化可特异性改变血管紧张素II的反应性，我们在高血压实验模型中确定了AT1受体的二聚化状态。与正常血压对照大鼠的细胞相比，从自发性高血压大鼠分离的肾系膜细胞上富含AT1/B2受体异二聚体。用受体特异性抗体进行免疫印迹分析确定，AT1与B2受体的异二聚化与高血压大鼠肾脏和系膜细胞上高水平的B2受体蛋白相关。对AT1/B2受体异二聚体的特异性抑制显示，这些受体异二聚体介导了血管紧张素II刺激的Gαq/11激活增强以及高血压大鼠系膜细胞内皮素-1分泌增加。因此，AT1/B2受体异二聚化促成了实验性高血压中系膜细胞对血管紧张素II的高反应性。
