Excess salt exacerbates blood-brain barrier disruption via a p38/MAPK/SGK1-dependent pathway in permanent cerebral ischemia.
Excess salt exacerbates blood-brain barrier disruption via a p38/MAPK/SGK1-dependent pathway in permanent cerebral ischemia.
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过量盐通过 p38/MAPK/SGK1 依赖性通路在永久性脑缺血中加剧血脑屏障破坏
DOI：
10.1038/srep16548
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发表时间：
2015-11-09
影响因子：
4.6
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Zhang T;Fang S;Wan C;Kong Q;Wang G;Wang S;Zhang H;Zou H;Sun B;Sun W;Zhang Y;Mu L;Wang J;Wang J;Zhang H;Wang D;Li H
高盐饮食（HSD）是导致包括缺血性中风在内的许多血管疾病的最重要的危险因素之一。一种提议的 HSD 介导的血脑屏障 (BBB) 破坏机制是通过间接提高血压来实现的。 HSD 对 BBB 完整性的直接作用尚不清楚。我们的目的是确定 HSD 是否以及如何参与缺血期间的 BBB 破坏。为了测试这一点，我们通过永久性大脑中动脉结扎（pMCAL）在正常饮食或HSD喂养的小鼠中诱导脑缺血模型。我们观察到，HSD 显着增强了缺血性脑损伤，这与 BBB 破坏增强、白细胞浸润增加和紧密连接 (TJ) 蛋白表达丧失相关，但血压没有明显改变。我们的体外实验还表明，氯化钠 (NaCl) 处理可下调内皮细胞的 TJ 蛋白表达，并显着增加饥饿期间的 BBB 通透性。抑制p38/MAPK/SGK1通路消除了NaCl对体外BBB通透性的影响。此外，我们注意到中风患者的尿钠水平与缺血性病变大小之间呈正相关。总之，我们的研究证明了 HSD 在缺血期间的独立于高血压的作用，并为脑缺血发作后的治疗提供了理论依据。
High salt diet (HSD) is one of the most important risk factors that contribute to many vascular diseases including ischemic stroke. One proposed mechanism underlying the disruption of blood-brain barrier (BBB) mediated by HSD is indirectly through enhancing blood pressure. The direct role of HSD on BBB integrity is unclear. Our purpose is to determine whether and how HSD might be involved in BBB breakdown during ischemia. To test that, we induced model of cerebral ischemia by permanent middle cerebral artery ligation (pMCAL) in either normal diet or HSD fed mice. We observed that HSD significantly enhanced ischemic brain damage which was associated with enhanced BBB disruption, increased leukocytes infiltration and loss of tight junction (TJ) proteins expression without apparently altering blood pressure. Ourin vitroexperiment also revealed that sodium chloride (NaCl) treatment down-regulated TJ protein expression by endothelial cells and substantially increased BBB permeability during starvation. Inhibition of p38/MAPK/SGK1 pathway eliminated the effect of NaCl on BBB permeabilityin vitro. In addition, we noticed a positive correlation between urinary sodium levels and ischemic lesion size in stroke patients. Together, our study demonstrates a hypertension-independent role of HSD during ischemia and provides rationale for post cerebral ischemic attack management.