Endothelin-2 Injures the Blood-Retinal Barrier and Macroglial Muller Cells Interactions with Angiotensin II, Aldosterone, and NADPH Oxidase
Endothelin-2 Injures the Blood-Retinal Barrier and Macroglial Muller Cells Interactions with Angiotensin II, Aldosterone, and NADPH Oxidase
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DOI：
10.1016/j.ajpath.2017.11.009
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发表时间：
2018-03-01
影响因子：
6
通讯作者：
Wilkinson-Berka, Jennifer L.
中科院分区：
文献类型：
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作者：
Alrashdi, Saeed F.;Deliyanti, Devy;Wilkinson-Berka, Jennifer L.
尽管越来越多的证据表明内皮素 2 (Edn2) 在组织病理学中具有独特的作用，包括炎症、神经胶质细胞功能障碍和血管生成，但它在视网膜中的作用以及调节其作用的因素尚未完全了解。我们假设 Edn2 会损害血视网膜屏障 (BRB)，这是通过与肾素-血管紧张素-醛固酮系统和 NADPH 氧化酶 (Nox) 衍生的活性氧相互作用介导的。 C57BL/6J 小鼠接受玻璃体内注射 Edn2 或对照载体，以检查 Edn2 的血压独立效应。给予 Edn2 的小鼠随机接受腹腔注射治疗，抑制 Edn a 型受体、Edn b 型受体、血管紧张素 1 型受体、盐皮质激素受体或 Nox 亚型 1 至 4。 一个月后，给予 Edn2 的小鼠表现出 BRB 破裂，血管渗漏增加、血管内皮生长因子表达增加和巨噬细胞浸润增加(Ly6C(+)CD45(高)CD11b(+))。此外，影响 BRB 完整性并防止视网膜水肿的大胶质细胞 Muller 细胞变成神经胶质细胞，并表达水通道 (aquaporin-4) 和离子通道 (Kir4.1) 水平增加。所有治疗均减少了这种 Edn2 介导的视网膜病变。对培养的 Muller 细胞进行的补充体外研究支持了这些发现，并证明了活性氧在介导这些事件中的重要性。总之，Edn2 对 BRB 和 Muller 细胞具有不利影响，涉及与肾素-血管紧张素醛固酮系统和 Nox1/4 的相互作用。
Although increasing evidence indicates that endothelin-2 (Edn2) has distinct roles in tissue pathology, including inflammation, glial cell dysfunction, and angiogenesis, its role in the retina and the factors that regulate its actions are not fully understood. We hypothesized that Edn2 damages the blood-retinal barrier (BRB) and that this is mediated by interactions with the renin-angiotensin-aldosterone system and reactive oxygen species derived from NADPH oxidase (Nox). C57BL/6J mice received an intravitreal injection of Edn2 or control vehicle to examine the blood pressure-independent effects of Edn2. Mice administered Edn2 were randomized to receive by intraperitoneal injection treatments that inhibited the Edn type a receptor, Edn type b receptor, angiotensin type 1 receptor, mineralocorticoid receptor, or Nox isoforms 1 to 4. One month later, mice administered Edn2 exhibited breakdown of the BRB with increased vascular leakage, vascular endothelial growth factor expression, and infiltrating macrophages (Ly6C(+)CD45(high)CD11b(+)). Further, macroglial Muller cells, which influence the integrity of the BRB and prevent retinal edema, became gliotic and expressed increased levels of water (aquaporin-4) and ion (Kir4.1) channels. This Edn2-mediated retinopathy was reduced by all treatments. Complementary in vitro studies in cultured Muller cells supported these findings and demonstrated the importance of reactive oxygen species in mediating these events. In conclusion, Edn2 has detrimental effects on the BRB and Muller cells that involve interactions with the renin-angiotensin aldosterone system and Nox1/4.