Wei Shun-Guang, Yu Yang, Zhang Zhi-Hua, Felder Robert B
Department of Internal Medicine, Univ. of Iowa College of Medicine, E318-GH, 200 Hawkins Dr., Iowa City, IA 52242, USA.
Am J Physiol Heart Circ Physiol. 2009 May;296(5):H1425-33. doi: 10.1152/ajpheart.00942.2008. Epub 2009 Mar 13.
ANG II type 1 receptors (AT(1)R) mediate most of the central effects of ANG II on cardiovascular function, fluid homeostasis, and sympathetic drive. The mechanisms regulating AT(1)R expression in the brain are unknown. In some tissues, the AT(1)R can be upregulated by prolonged exposure to ANG II. We examined the hypothesis that ANG II upregulates the AT(1)R in the brain by stimulating the intracellular mitogen-activated protein kinase (MAPK) signaling pathway. Using molecular and immunochemical approaches, we examined expression of the AT(1)R and phosphorylated MAPK in the paraventricular nucleus of the hypothalamus (PVN) and the subfornical organ (SFO) of rats receiving a chronic (4-wk) subcutaneous infusion of ANG II (0.6 microg/h) or saline (vehicle control), with or without concomitant (4-wk) intracerebroventricular (ICV) infusions of MAPK inhibitors or the AT(1)R blocker losartan. Subcutaneous infusion of ANG II markedly increased phosphorylation of MAPK and expression of AT(1)R mRNA and protein and AT(1)R-like immunoreactivity in the PVN and SFO. ANG II-induced AT(1)R expression was blocked by ICV infusion of the p44/42 MAPK inhibitor PD-98059 (0.025 microg/h) and the JNK inhibitor SP-600125 (0.125 microg/h), but not by the p38 MAPK inhibitor SB-203580 (0.125 microg/h). Upregulation of the AT(1)R in the PVN and SFO by peripheral ANG II was abolished by ICV losartan (10 microg/h). The data indicate that blood-borne ANG II upregulates brain AT(1)R by activating intracellular p44/42 MAPK and JNK signaling pathways.
血管紧张素II 1型受体（AT(1)R）介导血管紧张素II对心血管功能、体液平衡和交感神经驱动的大部分中枢效应。调节大脑中AT(1)R表达的机制尚不清楚。在一些组织中，长时间暴露于血管紧张素II可使AT(1)R上调。我们检验了血管紧张素II通过刺激细胞内丝裂原活化蛋白激酶（MAPK）信号通路来上调大脑中AT(1)R的假说。使用分子和免疫化学方法，我们检测了接受慢性（4周）皮下输注血管紧张素II（0.6微克/小时）或生理盐水（载体对照）的大鼠下丘脑室旁核（PVN）和穹窿下器官（SFO）中AT(1)R和磷酸化MAPK的表达，同时伴有或不伴有（4周）脑室内（ICV）输注MAPK抑制剂或AT(1)R阻滞剂氯沙坦。皮下输注血管紧张素II显著增加了PVN和SFO中MAPK的磷酸化以及AT(1)R mRNA、蛋白质的表达和AT(1)R样免疫反应性。脑室内输注p44/42 MAPK抑制剂PD - 98059（0.025微克/小时）和JNK抑制剂SP - 600125（0.125微克/小时）可阻断血管紧张素II诱导的AT(1)R表达，但p38 MAPK抑制剂SB - 203580（0.125微克/小时）则不能。脑室内氯沙坦（10微克/小时）可消除外周血管紧张素II对PVN和SFO中AT(1)R的上调作用。数据表明，血源性血管紧张素II通过激活细胞内p44/42 MAPK和JNK信号通路来上调大脑中的AT(1)R。
