Aquaporin-4 deletion ameliorates hypoglycemia-induced BBB permeability by inhibiting inflammatory responses.
Aquaporin-4 deletion ameliorates hypoglycemia-induced BBB permeability by inhibiting inflammatory responses.
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Aquaporin-4 缺失通过抑制炎症反应改善低血糖诱导的 BBB 通透性
DOI：
10.1186/s12974-018-1203-8
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发表时间：
2018-05-24
影响因子：
9.3
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Zhao F;Deng J;Xu X;Cao F;Lu K;Li D;Cheng X;Wang X;Zhao Y
重度低血糖通过上调水通道蛋白-4 （AQP4）表达和降解紧密连接诱导脑水肿。急性严重低血糖诱导促炎环境，可能通过降低紧密连接蛋白的表达导致上皮屏障的破坏。有趣的是，AQP4表达的改变被认为在急性脑损伤期间的神经炎症中起关键作用。已有研究表明，在脑内注射LPS后，AQP4缺失小鼠的脑炎症减少。然而，AQP4缺失在防止低血糖诱导的血脑屏障（BBB）破坏方面的作用尚不清楚。方法通过注射4单位/kg体重胰岛素建立急性严重低血糖应激模型。Evans blue （EB）染色和水分测定评估血脑屏障的通透性。Western blot、逆转录聚合酶链反应、免疫荧光检测相关蛋白的表达。通过酶联免疫吸附法评估细胞因子的产生。结果AQP4−/−小鼠低血糖诱导的脑水肿和血脑屏障渗漏减少。AQP4缺失上调PPAR-γ，抑制促炎反应。此外，在与内皮细胞共培养的星形细胞中，小干扰RNA敲低水通道蛋白-4可有效降低跨内皮细胞的渗透性和紧密连接的降解。用PPAR-γ抑制剂治疗表明，PPAR-γ上调是低血糖条件下AQP4缺失的保护作用的原因。结论AQP4缺失通过上调PPAR-γ的表达和抑制促炎细胞因子的释放来减少炎症反应，从而保护血脑屏障的完整性。AQP4的减少可能对急性严重低血糖有保护作用。
BackgroundSevere hypoglycemia induces brain edema by upregulating aquaporin-4 (AQP4) expression and by degrading tight junctions. Acute severe hypoglycemia induces a proinflammatory environment that may contribute to a disruption in the epithelial barrier by decreasing tight junction protein expression. Interestingly, the altered AQP4 expression has been considered to play a critical role in neuroinflammation during acute brain injury. It has been shown that AQP4 deletion reduces brain inflammation in AQP4-null mice after intracerebral LPS injection. However, the effect of AQP4 deletion regarding protection against hypoglycemia-induced blood-brain barrier (BBB) breakdown is unknown.MethodsAn acute severe hypoglycemic stress model was established via injection of 4 unit/kg body weight of insulin. Evans blue (EB) staining and water measurement were used to assess BBB permeability. Western blot, reverse transcription polymerase chain reaction, and immunofluorescence were used to detect the expression of related proteins. The production of cytokines was assessed via enzyme-linked immunosorbent assay.ResultsHypoglycemia-induced brain edema and BBB leakage were reduced in AQP4−/−mice. AQP4 deletion upregulated PPAR-γ and inhibited proinflammatory responses. Moreover, knockdown of aquaporin-4 by small interfering RNA in astrocytes co-cultured with endothelial cells effectively reduced transendothelial permeability and degradation of tight junctions. Treatment with PPAR-γ inhibitors showed that upregulation of PPAR-γ was responsible for the protective effect of AQP4 deletion under hypoglycemic conditions.ConclusionsOur data suggest that AQP4 deletion protects BBB integrity by reducing inflammatory responses due to the upregulation of PPAR-γ expression and attenuation of proinflammatory cytokine release. Reduction in AQP4 may be protective in acute severe hypoglycemia.
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