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Roles of endothelin receptors in astrocytic activation on brain pathologies

内皮素受体在脑病理学星形胶质细胞激活中的作用

基本信息

批准号：
12670086
负责人：
KOYAMA Yutaka
金额：
$ 2.11万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670086/
关键词：
Endothelin Astrocyte Brain injury Neurotrophic drug focal adhesion kinase neurotrophic factors

项目摘要

1. Endothelin-induced production of neurotrophic factors : Endothelin (ET) stimulated production of GDNF and BDNF, well-known neurotrophic factors, in rat cultured astorcytes. ET-induced GDNF production was inhibited by removal of intracellular Ca^<2+> and inhibition of ERK signal pathway. An inhibitor of NFkB (pyrrolidin dithiocarbamate) and pre-treatment with glucocorticoid had no effect on the ET-induced GDNF production, while GDNF production induced by H_2O_2 was prevented by them. Continuousinfusion of ETs into cerebral ventricle for 7 days increased GDNF and BDNF in hippocampus and striatum, respectively. Immunohistechemical examinations showed that these neurotrophic factors were produced by astrocytes. These findings suggest that activation of astrocytic ET receptors can be one target of neurotrophic drugs to stimulate neurotrophic factors.2. Endothelin-induced astrocytic proliferation : The mechanisms of ET-indeuced astrocytic proliferation by focusing roles of focal adhesion kinase (FAK), a tyrosine kinase associated with focal adhesions. ET stimulated phosphorylation of both FAK and ERK in astrocytes. Cytochalasin D inhibited ET-induced phosphorylation of FAK, but not that of ERK. Cytochalasin D reduced the incorporation of bromdeoxyuridine (BrdU) induced by ET-1. A transient transfection with wild-type FAK was followed byan increase in astrocytic BrdU incorporation. The effect of ET-1 on BrdU incorporation was diminished in astrocytes transfected with dominant-negative FAK mutants. ET-1 increased expression of cyclin D1 and D3 proteins in cultured astrocytes. Transfection with wild-type FAK increased expression of cyclin D3 in astrocytes, while that of cyclin D1 was not affected. The ET-induced increase in cyclin D3 expression, but not D1, was prevented by dominant-negative FAK mutants. These results suggest an involvement of FAK in astrocytic proliferation induced by ETs.

1.内皮素诱导的神经营养因子的产生：内皮素(ET)刺激大鼠培养的星形细胞中众所周知的神经营养因子GDNF和BDNF的产生。 ET诱导的GDNF产生通过细胞内Ca 2+ 的去除和ERK信号通路的抑制而受到抑制。 NFkB抑制剂(吡咯烷二硫代氨基甲酸酯)和糖皮质激素预处理对ET诱导的GDNF产生没有影响，而H_2O_2诱导的GDNF产生则被它们阻止。将ET连续注入脑室7天，分别增加海马和纹状体中的GDNF和BDNF。免疫组织化学检查表明这些神经营养因子是由星形胶质细胞产生的。这些发现表明星形细胞ET受体的激活可以成为神经营养药物刺激神经营养因子的靶点之一。2．内皮素诱导的星形细胞增殖：ET 诱导星形细胞增殖的机制是通过聚焦粘着斑激酶 (FAK)（一种与粘着斑相关的酪氨酸激酶）的作用。 ET 刺激星形胶质细胞中 FAK 和 ERK 的磷酸化。细胞松弛素 D 抑制 ET 诱导的 FAK 磷酸化，但不抑制 ERK 磷酸化。细胞松弛素 D 减少 ET-1 诱导的溴脱氧尿苷 (BrdU) 的掺入。野生型 FAK 瞬时转染后星形胶质细胞 BrdU 掺入量增加。在用显性失活 FAK 突变体转染的星形胶质细胞中，ET-1 对 BrdU 掺入的影响减弱。 ET-1 增加培养的星形胶质细胞中细胞周期蛋白 D1 和 D3 蛋白的表达。野生型FAK转染增加了星形胶质细胞中细胞周期蛋白D3的表达，而细胞周期蛋白D1的表达不受影响。 ET 诱导的细胞周期蛋白 D3 表达增加（而非 D1）被显性失活 FAK 突变体阻止。这些结果表明 FAK 参与 ET 诱导的星形胶质细胞增殖。