Seebach F A, Welte T, Fu X Y, Block L H, Kashgarian M
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06511-8023, USA.
Exp Mol Pathol. 2001 Jun;70(3):265-73. doi: 10.1006/exmp.2001.2361.
The vasoactive peptide angiotensin II is the principal effector of the renin-angiotensin system. It exerts mitogenic and growth-inhibiting effects in many target tissues, including renal mesangial cells. To investigate mechanisms of angiotensin II signaling in human mesangial cells, we explored the signal transducer and activator of transcription (STAT) pathway as a possible regulator of angiotensin II receptor-specific signaling. We tested whether angiotensin II could induce STAT activation and nuclear translocation of STAT proteins in human mesangial cells by electromobility shift assays and by immunostaining and confocal microscopy. We found that fetal human mesangial cells express STAT1,2,3,5, and 6 and that stimulation of these cells by angiotensin II results in rapid induction of STAT1 and STAT5 DNA-binding activity. This DNA-binding activity was identified as STAT5 for angiotensin receptor type 1 activation and STAT1 for angiotensin receptor type 2-mediated activation, as induction of STAT-DNA binding by angiotensin II could be differentially blocked by the angiotensin receptor type 1 blocker losartan and by angiotensin II receptor type 2 blocker PD 123,319. Angiotensin II also induced STAT1 and STAT5 tyrosine phosphorylation and nuclear translocation of activated STATs in a receptor subtype-specific manner. STAT activation thus appears to provide an important signaling pathway for angiotensin II-induced cellular responses.
血管活性肽血管紧张素II是肾素-血管紧张素系统的主要效应物。它在包括肾系膜细胞在内的许多靶组织中发挥促有丝分裂和生长抑制作用。为了研究血管紧张素II在人系膜细胞中的信号传导机制，我们探索了信号转导子和转录激活子（STAT）途径作为血管紧张素II受体特异性信号传导的一种可能调节因子。我们通过电泳迁移率变动分析以及免疫染色和共聚焦显微镜检查，测试血管紧张素II是否能诱导人系膜细胞中STAT的激活以及STAT蛋白的核转位。我们发现胎儿人系膜细胞表达STAT1、2、3、5和6，并且血管紧张素II对这些细胞的刺激导致STAT1和STAT5 DNA结合活性的快速诱导。这种DNA结合活性被确定为血管紧张素1型受体激活时的STAT5以及血管紧张素2型受体介导激活时的STAT1，因为血管紧张素II诱导的STAT-DNA结合可被血管紧张素1型受体阻滞剂氯沙坦和血管紧张素2型受体阻滞剂PD 123,319分别阻断。血管紧张素II还以受体亚型特异性方式诱导STAT1和STAT5酪氨酸磷酸化以及活化STAT的核转位。因此，STAT激活似乎为血管紧张素II诱导的细胞反应提供了一条重要的信号传导途径。
