Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood-brain water uptake and confers barrier function on perivascular astrocyte endfeet
Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood-brain water uptake and confers barrier function on perivascular astrocyte endfeet
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DOI：
10.1073/pnas.1110655108
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发表时间：
2011-10-25
影响因子：
11.1
通讯作者：
Nagelhus, Erlend Arnulf
中科院分区：
文献类型：
--
作者：
Haj-Yasein, Nadia Nabil;Vindedal, Gry Fluge;Nagelhus, Erlend Arnulf
需要对 Aqp4 基因进行组织和细胞特异性删除，才能区分众多的水通道蛋白 4 (AQP4) 水通道池。生成了神经胶质条件性 Aqp4 敲除小鼠系，以解决星形胶质细胞 AQP4 是否控制血脑界面的水交换。条件敲除是由神经胶质原纤维酸性蛋白启动子驱动的。通过蛋白质印迹评估，条件性 Aqp4 敲除的大脑缺乏 AQP4，从而排除了显着的 AQP4 内皮库的存在。冷冻切片的免疫荧光分析和超薄切片的定量免疫金分析一致显示毛细血管内皮中没有 AQP4 信号。与同窝对照相比，神经胶质条件性 Aqp4 基因敲除小鼠在全身低渗应激后脑水摄取量减少 31%，并且出生后脑水吸收延迟。星形胶质细胞Aqp4的缺失并不影响大分子的屏障功能。我们的数据表明血脑屏障（BBB）比预期的更复杂。值得注意的是，在某些条件下，脑微血管的星形胶质细胞覆盖对水运动的速率进行限制。
Tissue-and cell-specific deletion of the Aqp4 gene is required to differentiate between the numerous pools of aquaporin-4 (AQP4) water channels. A glial-conditional Aqp4 knockout mouse line was generated to resolve whether astroglial AQP4 controls water exchange across the blood-brain interface. The conditional knockout was driven by the glial fibrillary acidic protein promoter. Brains from conditional Aqp4 knockouts were devoid of AQP4 as assessed by Western blots, ruling out the presence of a significant endothelial pool of AQP4. In agreement, immunofluorescence analysis of cryostate sections and quantitative immunogold analysis of ultrathin sections revealed no AQP4 signals in capillary endothelia. Compared with litter controls, glial-conditional Aqp4 knockout mice showed a 31% reduction in brain water uptake after systemic hypoosmotic stress and a delayed postnatal resorption of brain water. Deletion of astroglial Aqp4 did not affect the barrier function to macromolecules. Our data suggest that the blood-brain barrier (BBB) is more complex than anticipated. Notably, under certain conditions, the astrocyte covering of brain microvessels is rate limiting to water movement.