Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-κB pathway
Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-κB pathway
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DOI：
10.1167/iovs.06-1473
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发表时间：
2007-09-01
影响因子：
4.4
通讯作者：
Ishida, Susumu
中科院分区：
文献类型：
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作者：
Nagai, Norihiro;Izumi-Nagai, Kanako;Ishida, Susumu
目的。探讨肾素-血管紧张素系统（RAS）和核因子（NF）-κB通路与糖尿病引起的视网膜炎症的关系。诱导糖尿病六周后，C57BL/6 小鼠每天接受血管紧张素 II 1 型受体 (AT1-R) 阻断剂 (ARB) 替米沙坦或缬沙坦、AT2-R 阻断剂 PD123319 或 NF-κ B 抑制剂脱羟甲基环氧喹诺星 (DHMEQ) 治疗，持续 1 周。分别通过 RT-PCR 和蛋白质印迹检查视网膜 RAS 成分的 mRNA 和蛋白质水平。用伴刀豆球蛋白 A 凝集素灌注标记技术评估白细胞对视网膜脉管系统的粘附力。采用RT-PCR和ELISA检测视网膜细胞间粘附分子(ICAM)-1和血管内皮生长因子(VEGF)的表达水平。将 ARB 或 DHMEQ 应用于高浓度葡萄糖刺激的小鼠毛细血管内皮 (b-End3) 细胞，通过免疫组织化学分析 NF-κ B 的核转位，检测 p65 以及 ICAM-1 和单核细胞趋化蛋白 (MCP)-1 的 mRNA 和蛋白水平。结果。糖尿病的诱导导致视网膜表达和 RAS 成分（包括血管紧张素 II、AT1-R 和 AT2-R）的产生显着增加。 AT1-R 阻断显着抑制视网膜贴壁白细胞，但 AT2-R 阻断则不显着抑制。施用 ARB（而非 PD123319）可抑制糖尿病诱导的视网膜 ICAM-1 和 VEGF 表达。 DHMEQ 还将糖尿病视网膜中的这些细胞和分子炎症参数抑制到 ARB 治疗所获得的水平。在体外，ARB 的应用显着抑制了葡萄糖诱导的 NF-κ B p65 核转位以及 ICAM-1 和 MCP-1 的上调。 ARB 以及 DHMEQ 的体内治疗本身就减弱了糖尿病诱导的视网膜血管紧张素 II 和 AT1-R 的表达。结论。目前的数据揭示了 AT1-R/NF-kappa B 通路对糖尿病引起的视网膜炎症的显着贡献，为靶向 AT1-R 或 NF-kappa B 治疗糖尿病视网膜病变提供了机制原因。
PURPOSE. To investigate the involvement of the renin-angiotensin system (RAS) and the nuclear factor (NF)-kappa B pathway with diabetes-induced retinal inflammation.METHODS. Six weeks after induction of diabetes, C57BL/6 mice were treated with the angiotensin II type 1 receptor (AT1-R) blocker (ARB) telmisartan or valsartan, the AT2-R blocker PD123319, or the NF-kappa B inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) daily for 1 week. Retinal mRNA and protein levels of the RAS components were examined by RT-PCR and Western blot, respectively. Leukocyte adhesion to the retinal vasculature was evaluated with a concanavalin A lectin perfusion-labeling technique. Retinal expression levels of intercellular adhesion molecule (ICAM)-1 and vascular endothelial growth factor ( VEGF) were examined by RT-PCR and ELISA. ARB or DHMEQ was applied to murine capillary endothelial (b-End3) cells stimulated with a high concentration of glucose to analyze nuclear translocation of NF-kappa B via immunohistochemistry for p65 and mRNA and protein levels of ICAM-1 and monocyte chemotactic protein (MCP)-1.RESULTS. Induction of diabetes led to a significant increase in retinal expression and production of the RAS components including angiotensin II, AT1-R, and AT2-R. Retinal adherent leukocytes were significantly suppressed by AT1-R, but not by AT2-R, blockade. Administration of the ARB, but not of PD123319, inhibited diabetes-induced retinal expression of ICAM-1 and VEGF. DHMEQ also suppressed these cellular and molecular inflammatory parameters in the diabetic retina to the levels obtained with ARB treatment. In vitro, glucose-induced nuclear translocation of NF-kappa B p65 and upregulation of ICAM-1 and MCP-1 were significantly suppressed by application of the ARB. The in vivo treatment with the ARB, as well as DHMEQ, attenuated the diabetes-induced retinal expression of angiotensin II and AT1-R, per se.CONCLUSIONS. The present data revealed significant a contribution of the AT1-R/NF-kappa B pathway to diabetes-induced retinal inflammation, providing a mechanistic reason for targeting AT1-R or NF-kappa B in the treatment of diabetic retinopathy.