Nestoridi Eirini, Kushak Rafail I, Tsukurov Olga, Grabowski Eric F, Ingelfinger Julie R
Pediatric Nephrology Laboratory, MassGeneral Hospital for Children at Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Pediatr Nephrol. 2008 Feb;23(2):221-31. doi: 10.1007/s00467-007-0636-6. Epub 2007 Nov 30.
Current evidence implicates a prothrombotic state in the development of Shiga-toxin (Stx)-mediated hemolytic uremic syndrome (HUS). We recently reported that Stx modulates procoagulant activity by enhancing functional tissue factor (TF) activity on cytokine-activated human glomerular endothelial cells (HGECs). Since angiotensin II (Ang II), the key effector of the renin angiotensin system (RAS), has been shown to increase TF expression in vascular tissue, we examined the possible involvement of Ang II in TF expression in HGECs. HGECs were exposed to tumor necrosis factor (TNF)-alpha +/- Stx-1 +/- Ang II. Exogenous Ang II significantly increased TF activity and TF mRNA in TNF-alpha- +/- Stx-1-activated HGECs. This increase was mediated via Ang II type I receptor (AT(1)R), as losartan, an AT(1)R inhibitor, attenuated Ang-II-induced TF activity. To study the effect of endogenous Ang II in TF expression by TNF-alpha +/- Stx-1, HGECs were incubated with losartan or an AT(2)R inhibitor (PD 123319) or an angiotensin-converting enzyme inhibitor (enalapril). Losartan but not PD 123319 decreased TF activity induced by TNF-alpha +/- Stx-1 (P < 0.05). Enalapril, also, dose dependently, downregulated TF expression in HGECs exposed to TNF-alpha +/- Stx-1 (P < 0.05). AT(1)R mRNA was upregulated in TNF-alpha- +/- Stx-1-activated HGECs (P < 0.05). These data indicate that TF expression in TNF-alpha- and Stx-1-activated HGECs is enhanced by exogenous Ang II and that endogenous Ang II production may be upregulated by TNF-alpha +/- Stx-1. Hence, local RAS activation may be important in the development of the thrombotic microangiopathy observed in HUS.
目前的证据表明，促血栓形成状态与志贺毒素（Stx）介导的溶血尿毒综合征（HUS）的发生有关。我们最近报道，Stx通过增强细胞因子激活的人肾小球内皮细胞（HGECs）上功能性组织因子（TF）的活性来调节促凝血活性。由于肾素血管紧张素系统（RAS）的关键效应因子血管紧张素II（Ang II）已被证明可增加血管组织中TF的表达，我们研究了Ang II在HGECs中TF表达的可能作用。将HGECs暴露于肿瘤坏死因子（TNF）-α+/- Stx-1+/- Ang II。外源性Ang II显著增加了TNF-α+/- Stx-1激活的HGECs中的TF活性和TF mRNA。这种增加是通过I型Ang II受体（AT(1)R）介导的，因为AT(1)R抑制剂氯沙坦减弱了Ang II诱导的TF活性。为了研究内源性Ang II对TNF-α+/- Stx-1诱导的TF表达的影响，将HGECs与氯沙坦或AT(2)R抑制剂（PD 123319）或血管紧张素转换酶抑制剂（依那普利）一起孵育。氯沙坦而非PD 123319降低了TNF-α+/- Stx-1诱导的TF活性（P < 0.05）。依那普利也剂量依赖性地下调了暴露于TNF-α+/- Stx-1的HGECs中的TF表达（P < 0.05）。在TNF-α+/- Stx-1激活的HGECs中，AT(1)R mRNA上调（P < 0.05）。这些数据表明，外源性Ang II增强了TNF-α和Stx-1激活的HGECs中的TF表达，并且内源性Ang II的产生可能被TNF-α+/- Stx-1上调。因此，局部RAS激活可能在HUS中观察到的血栓性微血管病的发生中起重要作用。
