Redistribution of aquaporin-4 in human glioblastoma correlates with loss of agrin immunoreactivity from brain capillary basal laminae
Redistribution of aquaporin-4 in human glioblastoma correlates with loss of agrin immunoreactivity from brain capillary basal laminae
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DOI：
10.1007/s00401-003-0812-0
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发表时间：
2004-04-01
影响因子：
12.7
通讯作者：
Wolburg, H
中科院分区：
文献类型：
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作者：
Warth, A;Kröger, S;Wolburg, H
血管源性水肿是脑肿瘤中最严重的临床问题之一，并且与脑中不同液体隔室之间的水转移密切相关。已经认识到水通道蛋白水通道对脑中水肿性肿胀的发展具有重要影响。星形胶质细胞被认为诱导或至少维持脑毛细血管内皮细胞中的血脑屏障，其表达水通道蛋白同种型AQP 4。通常，AQP 4高度集中在星形胶质细胞接触间充质空间的神经胶质膜中，例如血管周围或脑表面区域。实质膜不显示任何免疫细胞化学AQP 4特异性信号。我们研究了AQP 4在人胶质母细胞瘤中的表达，并将其与细胞外硫酸乙酰肝素蛋白聚糖聚集蛋白和肌营养不良蛋白-肌营养不良蛋白聚糖复合物的成员的表达模式相关联。我们发现AQP 4完全覆盖胶质瘤细胞的表面。α-肌营养不良聚糖不存在于神经胶质膜中，但保留在内皮膜中。Utrophin和dystrophin在AQP 4重新分布的细胞中仍然局限于端足膜，而α-突触营养蛋白与AQP 4一起重新分布在整个细胞表面。由于α-肌营养不良蛋白聚糖作为聚集蛋白的结合蛋白起作用，这些观察结果支持以下建议：（1）AQP 4与肌营养不良蛋白-肌营养不良蛋白聚糖复合物紧密相关，以及（2）聚集蛋白是星形胶质细胞中AQP 4极化分布所必需的。结果进行了讨论的事实，通常AQP 4组装在所谓的正交阵列的颗粒（OAPs）的限制AQP 4/OAPs的终足膜可能依赖于聚集蛋白的存在，这可能是本质上连接到星形胶质细胞的能力，以维持血脑屏障的完整性。
Vasogenic edema is one of the most serious clinical problems in brain tumors and tightly connected to water shifts between the different fluid compartments in the brain. Aquaporin water channels have been recognized to have an important impact on the development of edematous swelling in the brain. Astrocytes, which are believed to induce or at least maintain the blood-brain barrier in the brain capillary endothelial cells, express the aquaporin isoform AQP4. Normally, AQP4 is highly concentrated in the glial membrane where astrocytes contact mesenchymal space, such as perivascular or brain superficial regions. Parenchymal membranes do not show any immunocytochemical AQP4-specific signal. We investigated the AQP4 expression in human glioblastoma and correlated it with the expression pattern of the extracellular heparan sulfate proteoglycan agrin and members of the dystrophin-dystroglycan complex. We found that AQP4 completely covered the surface of the glioma cells. alpha-Dystroglycan was absent from glial membranes but retained in endothelial membranes. Utrophin and dystrophin remained restricted to the endfoot membrane in those cells in which AQP4 had been redistributed, whereas alpha-syntrophin redistributed together with AQP4 across the entire cell surface. Since alpha-dystroglycan operates as a binding protein for agrin, these observations support the suggestions that (1) AQP4 is tightly associated with the dystrophin-dystroglycan complex, and (2) agrin is necessary for the polarized distribution of AQP4 in the astrocyte. The results are discussed in connection with the fact that normally AQP4 is assembled in the so-called orthogonal arrays of particles (OAPs).The restriction of AQP4/OAPs to the endfoot membrane may be dependent on the presence of agrin, and this might be essentially connected to the ability of astrocytes to maintain the integrity of the blood-brain barrier.