Erythropoietin protects against hemorrhagic blood-brain barrier disruption through the effects of aquaporin-4
Erythropoietin protects against hemorrhagic blood-brain barrier disruption through the effects of aquaporin-4
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促红细胞生成素通过水通道蛋白-4 的作用防止出血性血脑屏障破坏
DOI：
10.1038/labinvest.2014.84
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发表时间：
2014-09-01
影响因子：
5
通讯作者：
Dong, Qiang
中科院分区：
文献类型：
--
作者：
Chu, Heling;Ding, Hongyan;Dong, Qiang
促红细胞生成素（EPO）对许多神经系统疾病具有保护作用，包括脑出血（ICH）。在这里，我们的目的是测试EPO对脑出血后血脑屏障（BBB）破坏的形态和功能的影响，这还没有得到很好的研究。我们还研究了这种作用是否依赖于水通道蛋白4（AQP 4）。于脑出血后1、3、7天检测血肿周围AQP 4和EPO受体（EPOR）的表达。我们还研究了EPO对野生型小鼠脑出血引起的血脑屏障破坏的作用，并通过使用AQP 4基因敲除小鼠测试了这种作用是否依赖于AQP 4。此外，我们评估了相关的信号转导途径，通过星形胶质细胞培养。我们发现，EPO高度增加血肿周围AQP 4和EPOR的表达。具体而言，EPO通过在功能上减少脑水肿和BBB通透性，以及在形态上抑制紧密连接（TJ）开放和内皮细胞肿胀，并增加TJ蛋白闭合蛋白和闭合小带-1（ZO-1）的表达，在两种类型的小鼠中导致BBB保护。统计分析表明，这些作用需要AQP 4。此外，EPO上调C-Jun氨基末端激酶（JNK）和p38丝裂原活化蛋白激酶（MAPK）以及EPOR和AQP 4蛋白在培养的星形胶质细胞的磷酸化。后者可被JNK和p38-MAPK抑制剂抑制。我们的数据表明，EPO保护血脑屏障破裂后，脑出血和主要目标是TJ蛋白occludin和ZO-1。EPO的作用与AQP 4水平的增加有关，并且可能在与EPOR结合后通过激活JNK和p38-MAPK通路而发生。
Erythropoietin (EPO) has protective effects against many neurological diseases, including intracerebral hemorrhage (ICH). Here, we aimed to test EPO's effects on blood brain barrier (BBB) disruption morphologically and functionally following ICH, which has not been well investigated. We also examined whether the effects were dependent on aquaporin-4 (AQP4). We detected the expression of perihematomal AQP4 and EPO receptor (EPOR) induced by EPO injection at 1, 3 and 7 days after ICH. We also examined the effects of EPO on BBB disruption by ICH in wild-type mice, and tested whether such effects were AQP4 dependent by using AQP4 knock-out mice. Furthermore, we assessed the related signal transduction pathways via astrocyte cultures. We found that EPO highly increased perihematomal AQP4 and EPOR expression. Specifically, EPO led to BBB protection in both types of mice by functionally reducing brain edema and BBB permeability, as well as morphologically suppressing tight junction (TJ) opening and endothelial cell swelling, and increasing expression of the TJ proteins occludin and zonula occluden-1 (ZO-1). Statistical analysis indicated that AQP4 was required for these effects. In addition, EPO upregulated phosphorylation of C-Jun amino-terminal kinase (JNK) and p38-mitogen-activated protein kinase (MAPK) as well as EPOR and AQP4 proteins in cultured astrocytes. The latter was inhibited by JNK and p38-MAPK inhibitors. Our data suggest that EPO protects BBB from disruption after ICH and that the main targets are the TJ proteins occludin and ZO-1. The effects of EPO are associated with increased levels of AQP4, and may occur through activation of JNK and p38-MAPK pathways after binding to EPOR.