Involvement of Mitogen-Activated Protein Kinase Pathways in Expression of the Water Channel Protein Aquaporin-4 after Ischemia in Rat Cortical Astrocytes
Involvement of Mitogen-Activated Protein Kinase Pathways in Expression of the Water Channel Protein Aquaporin-4 after Ischemia in Rat Cortical Astrocytes
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DOI：
10.1089/neu.2012.2430
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发表时间：
2012-09-01
影响因子：
4.2
通讯作者：
Chan, Pak H.
中科院分区：
文献类型：
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作者：
Nito, Chikako;Kamada, Hiroshi;Chan, Pak H.
缺血性脑损伤后脑水肿是发病率和死亡率的关键决定因素。水通道蛋白-4 （Aquaporin-4, AQP4）在中枢神经系统的水转运中起重要作用，在脑星形胶质细胞中高表达。然而，人们对AQP4的调控机制知之甚少。在本研究中，我们研究了参与渗透变化的丝裂原活化蛋白激酶（MAPKs）是否可能介导大鼠皮质星形胶质细胞缺血后AQP4的表达。原代培养的星形胶质细胞经氧糖剥夺（OGD）和2 h再氧化后AQP4水平升高，在0 h再氧化后AQP4水平立即下降。OGD损伤的星形胶质细胞中三种MAPKs的磷酸化水平显著升高。用选择性p38 MAPK抑制剂SB203580或选择性c-Jun n -末端激酶抑制剂SP600125显著降低AQP4恢复到正常水平，并且SB203580显著降低细胞死亡，而SP600125没有。在体内研究中，AQP4在再灌注后1-3天表达上调，与p38磷酸化活化的时间过程一致，并在短暂性大脑中动脉闭塞（MCAO）后因p38抑制而表达下调。提示p38 MAPK可能调控脑皮质星形胶质细胞缺血损伤后AQP4的表达。
Brain edema after ischemic brain injury is a key determinant of morbidity and mortality. Aquaporin-4 (AQP4) plays an important role in water transport in the central nervous system and is highly expressed in brain astrocytes. However, the AQP4 regulatory mechanisms are poorly understood. In this study, we investigated whether mitogen-activated protein kinases (MAPKs), which are involved in changes in osmolality, might mediate AQP4 expression in models of rat cortical astrocytes after ischemia. Increased levels of AQP4 in primary cultured astrocytes subjected to oxygen-glucose deprivation (OGD) and 2 h of reoxygenation were observed, after which they immediately decreased at 0 h of reoxygenation. Astrocytes exposed to OGD injury had significantly increased phosphorylation of three kinds of MAPKs. Treatment with SB203580, a selective p38 MAPK inhibitor, or SP600125, a selective c-Jun N-terminal kinase inhibitor, significantly attenuated the return of AQP4 to its normal level, and SB203580, but not SP600125, significantly decreased cell death. In an in vivo study, AQP4 expression was upregulated 1-3 days after reperfusion, which was consistent with the time course of p38 phosphorylation and activation, and decreased by the p38 inhibition after transient middle cerebral artery occlusion (MCAO). These results suggest that p38 MAPK may regulate AQP4 expression in cortical astrocytes after ischemic injury.