Morimoto Satoshi, Cassell Martin D, Sigmund Curt D
Department of Internal Medicine and Physiology & Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
J Biol Chem. 2002 Sep 6;277(36):33235-41. doi: 10.1074/jbc.M204309200. Epub 2002 Jun 21.
The purpose of this study is to examine the regulation of blood pressure and fluid and electrolyte homeostasis in mice overexpressing angiotensin II (Ang-II) in the brain and to determine whether there are significant physiologic differences in Ang-II production in neurons or glia. Therefore, we generated and characterized transgenic mice overexpressing human renin (hREN) under the control of the glial fibrillary acidic protein (GFAP) promoter (GFAP-hREN) and synapsin-I promoter (SYN-hREN) and bred them with mice expressing human angiotensinogen (hAGT) under the control of the same promoters (GFAP-hAGT and SYN-hAGT). Both GFAP-hREN and SYN-hREN mice exhibited the highest hREN mRNA expression in the brain and had undetectable levels of hREN protein in the systemic circulation. In the brain of GFAP-hREN and SYN-hREN mice, hREN protein was observed almost exclusively in astrocytes and neurons, respectively. Transgenic mice overexpressing both hREN and hAGT transgenes in either glia or neurons were moderately hypertensive. In the glia-targeted mice, blood pressure could be corrected by intracerebroventricular injection of the Ang-II type 1 receptor antagonist losartan, and intravenous injection of a ganglion blocking agent, but not an arginine vasopressin V1 receptor antagonist, lowered blood pressure. These data suggest that stimulation of Ang-II type 1 receptors in the brain by Ang-II derived from local synthesis of renin and angiotensinogen can cause an elevation in blood pressure via a mechanism involving enhanced sympathetic outflow. Glia- and neuron-targeted mice also exhibited an increase in drinking volume and salt preference, suggesting that chronic overexpression of renin and angiotensinogen locally in the brain can result in hypertension and alterations in fluid homeostasis.
本研究的目的是研究脑内过表达血管紧张素II（Ang-II）的小鼠的血压调节以及液体和电解质稳态，并确定神经元或胶质细胞中Ang-II产生是否存在显著的生理差异。因此，我们构建并鉴定了在胶质纤维酸性蛋白（GFAP）启动子（GFAP-hREN）和突触素-I启动子（SYN-hREN）控制下过表达人肾素（hREN）的转基因小鼠，并将它们与在相同启动子（GFAP-hAGT和SYN-hAGT）控制下表达人血管紧张素原（hAGT）的小鼠进行杂交。GFAP-hREN和SYN-hREN小鼠在脑中均表现出最高的hREN mRNA表达，且在体循环中检测不到hREN蛋白。在GFAP-hREN和SYN-hREN小鼠的脑中，hREN蛋白几乎分别仅在星形胶质细胞和神经元中观察到。在胶质细胞或神经元中过表达hREN和hAGT转基因的小鼠均有中度高血压。在以胶质细胞为靶点的小鼠中，脑室内注射Ang-II 1型受体拮抗剂氯沙坦可纠正血压，静脉注射神经节阻断剂可降低血压，但精氨酸加压素V1受体拮抗剂则不能。这些数据表明，由肾素和血管紧张素原局部合成产生的Ang-II刺激脑内的Ang-II 1型受体，可通过涉及增强交感神经传出的机制导致血压升高。以胶质细胞和神经元为靶点的小鼠还表现出饮水量增加和对盐的偏好增加，这表明脑内局部慢性过表达肾素和血管紧张素原可导致高血压和液体稳态改变。
