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Abstract：
BACKGROUND: Astrocytes are the most abundant cell type of the central nervous system and are fundamentally involved in homeostasis, neuroprotection, and synaptic plasticity. This regulatory function of astrocytes on their neighboring cells in the healthy brain is subject of current research. In the ischemic brain we assume disease specific differences in astrocytic acting. The renin-angiotensin-aldosterone system regulates arterial blood pressure through endothelial cells and perivascular musculature. Moreover, astrocytes express angiotensin II type 1 and 2 receptors. However, their role in astrocytic function has not yet been fully elucidated. We hypothesized that the angiotensin II receptors impact astrocyte function as revealed in an in vitro system mimicking cerebral ischemia. Astrocytes derived from neonatal wistar rats were exposed to telmisartan (angiotensin II type 1 receptor-blocker) or PD123319 (angiotensin II type 2 receptor-blocker) under normal conditions (control) or deprivation from oxygen and glucose. Conditioned medium (CM) of astrocytes was harvested to elucidate astrocyte-mediated indirect effects on microglia and cortical neurons.
RESULTS: The blockade of angiotensin II type 1 receptor by telmisartan increased the survival of astrocytes during ischemic conditions in vitro without affecting their proliferation rate or disturbing their expression of S100A10, a marker of activation. The inhibition of the angiotensin II type 2 receptor pathway by PD123319 resulted in both increased expression of S100A10 and proliferation rate. The CM of telmisartan-treated astrocytes reduced the expression of pro-inflammatory mediators with simultaneous increase of anti-inflammatory markers in microglia. Increased neuronal activity was observed after treatment of neurons with CM of telmisartan- as well as PD123319-stimulated astrocytes.
CONCLUSIONS: Data show that angiotensin II receptors have functional relevance for astrocytes that differs in healthy and ischemic conditions and effects surrounding microglia and neuronal activity via secretory signals. Above that, this work emphasizes the strong interference of the different cells in the CNS and that targeting astrocytes might serve as a therapeutic strategy to influence the acting of glia-neuronal network in de- and regenerative context.
RESULTS: The blockade of angiotensin II type 1 receptor by telmisartan increased the survival of astrocytes during ischemic conditions in vitro without affecting their proliferation rate or disturbing their expression of S100A10, a marker of activation. The inhibition of the angiotensin II type 2 receptor pathway by PD123319 resulted in both increased expression of S100A10 and proliferation rate. The CM of telmisartan-treated astrocytes reduced the expression of pro-inflammatory mediators with simultaneous increase of anti-inflammatory markers in microglia. Increased neuronal activity was observed after treatment of neurons with CM of telmisartan- as well as PD123319-stimulated astrocytes.
CONCLUSIONS: Data show that angiotensin II receptors have functional relevance for astrocytes that differs in healthy and ischemic conditions and effects surrounding microglia and neuronal activity via secretory signals. Above that, this work emphasizes the strong interference of the different cells in the CNS and that targeting astrocytes might serve as a therapeutic strategy to influence the acting of glia-neuronal network in de- and regenerative context.
摘要：
背景：星形胶质细胞是中枢神经系统中最丰富的细胞类型，并且从根本上参与稳态，神经保护,和突触可塑性。星形胶质细胞对健康大脑中相邻细胞的这种调节功能是当前研究的主题。在缺血性脑中，我们假设星形细胞作用的疾病特异性差异。肾素-血管紧张素-醛固酮系统通过内皮细胞和血管周围肌肉组织调节动脉血压。此外，星形胶质细胞表达血管紧张素II1型和2型受体。然而,它们在星形细胞功能中的作用尚未完全阐明。我们假设血管紧张素II受体影响星形胶质细胞功能，如在模拟脑缺血的体外系统中所揭示的那样。在正常条件（对照）或缺乏氧气和葡萄糖的情况下，将来自新生wistar大鼠的星形胶质细胞暴露于替米沙坦（血管紧张素II1型受体阻滞剂）或PD123319（血管紧张素II2型受体阻滞剂）。收获星形胶质细胞的条件培养基（CM）以阐明星形胶质细胞介导的对小胶质细胞和皮质神经元的间接影响。
结果：替米沙坦阻断血管紧张素II1型受体在体外缺血条件下增加了星形胶质细胞的存活，而不影响其增殖率或干扰其激活标志物S100A10的表达。PD123319对血管紧张素II2型受体途径的抑制导致S100A10的表达和增殖率增加。替米沙坦治疗的星形胶质细胞的CM降低了促炎介质的表达，同时增加了小胶质细胞中的抗炎标志物。用telmisartan和PD123319刺激的星形胶质细胞的CM处理神经元后，观察到神经元活性增加。
结论：数据显示，血管紧张素II受体对星形胶质细胞具有功能相关性，在健康和缺血条件下不同，并通过分泌信号影响小胶质细胞和神经元活动。在这上面，这项工作强调了中枢神经系统中不同细胞的强烈干扰,并且靶向星形胶质细胞可能作为一种治疗策略,在去再生和再生环境中影响神经胶质神经元网络的作用.
结果：替米沙坦阻断血管紧张素II1型受体在体外缺血条件下增加了星形胶质细胞的存活，而不影响其增殖率或干扰其激活标志物S100A10的表达。PD123319对血管紧张素II2型受体途径的抑制导致S100A10的表达和增殖率增加。替米沙坦治疗的星形胶质细胞的CM降低了促炎介质的表达，同时增加了小胶质细胞中的抗炎标志物。用telmisartan和PD123319刺激的星形胶质细胞的CM处理神经元后，观察到神经元活性增加。
结论：数据显示，血管紧张素II受体对星形胶质细胞具有功能相关性，在健康和缺血条件下不同，并通过分泌信号影响小胶质细胞和神经元活动。在这上面，这项工作强调了中枢神经系统中不同细胞的强烈干扰,并且靶向星形胶质细胞可能作为一种治疗策略,在去再生和再生环境中影响神经胶质神经元网络的作用.
