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Angiotensin II inside and outside the brain: investigation on the mechanism of angiotensin II-induced

脑内外血管紧张素II：血管紧张素II诱导机制研究

基本信息

批准号：
17590593
负责人：
MIYOSHI Michio
金额：
$ 2.11万
依托单位：
Tottori University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590593/
关键词：
ANG II LPS cytokines microglial cell NF-κB AP-1 NO morphological change 視床下部海馬発熱

项目摘要

We investigated whether proinflammatory transcription factors [nuclear factor-κB (NF-κB) and activator protein-1 (AP-1)] contribute to the angiotensin II (ANG II)-dependent production of cytokines within the brain. Interestingly, we found that a single i.c.v. injection of lipopolysaccharide (LPS) had no effect on NF-κB and AP-1 activities in the hypothalamus, hippocampus, and cerebellum (except for a decrease in hypothalamic AP-1 activity). Furthermore, both an angiotensin-converting-enzyme (ACE) inhibitor and an ANG type 1 (AT_1) receptor antagonist enhanced (rather than reduced) the NF-κB and AP-1 activities in the hippocampus and/or cerebellum of rats given LPS. These results seem not to support the idea that NF-κB and AP-1 play key roles in the ANG II-induced enhancement of the production of proinflammatory cytokines that is induced by LPS in the rat's brain. However, only a portion of whole brain cells is occupied by brain macrophage, microglial cells. Therefore, we then investiga … More ted whether ANG II and its receptors contributes to LPS-induced microglial activations through their effect on the activation of NF-κB and AP-1. To this end, examined were the effects of an ATI receptor antagonist, losartan, on the LPS-induced productions of interleukin-1 (IL-1) and nitric oxide (NO), morphological changes of the cells, as well as the activations of NF-κB and AP-1 in primary culture of microglial cells. Our RT-PCR study revealed that LPS-stimulated microglial cells had marked expression of mRNAs for ATI receptor. LPS-stimulated microglial cells showed increases in IL-1 and nitrite concentrations, as well as a morphological change. These effects were all inhibited by treatment with losartan. The activity of NF-κB and AP-1 was enhanced in LPS-stimulated microglial cells, that were significantly suppressed by losartan. Application of ANG II itself enhanced the LPS-induced increase in nitrite concentration. Collectively, these results suggest that the production of pyrogenic cytokines may be enhanced by ANG II and AT_1 receptor that stimulate microglial cells through the activation of transcription factors, NF-κB and AP-1 Less

我们研究了促炎性转录因子[核因子-κB（NF-κB）和激活蛋白-1（AP-1）]是否有助于脑内血管紧张素II（ANG II）依赖性细胞因子的产生。有趣的是，我们发现单次静脉注射脂多糖（LPS）对下丘脑、海马和小脑中的NF-κB和AP-1活性没有影响（除了下丘脑AP-1活性降低）。此外，血管紧张素转换酶（ACE）抑制剂和血管紧张素1型受体（AT_1）拮抗剂均能增强（而非降低）LPS诱导的大鼠海马和/或小脑中NF-κB和AP-1的活性。这些结果似乎不支持NF-κB和AP-1在ANG II诱导的LPS诱导的大鼠脑中促炎细胞因子产生的增强中起关键作用的观点。然而，整个脑细胞中只有一部分被脑巨噬细胞、小胶质细胞占据。因此，我们 ...更多信息研究ANG II及其受体是否通过影响NF-κB和AP-1的活化而参与LPS诱导的小胶质细胞活化。本研究观察了ATI受体拮抗剂Losartan对LPS诱导的小胶质细胞产生白细胞介素-1（IL-1）和一氧化氮（NO）、细胞形态学改变以及NF-κB和AP-1活化的影响。我们的RT-PCR研究显示，LPS刺激的小胶质细胞具有ATI受体的mRNA的显着表达。LPS刺激的小胶质细胞显示IL-1和亚硝酸盐浓度增加，以及形态学变化。这些作用均被氯沙坦抑制。LPS刺激的小胶质细胞NF-κB和AP-1的活性增强，而Losartan则显著抑制。ANG II本身的应用增强了LPS诱导的亚硝酸盐浓度的增加。总之，这些结果表明，ANG II和AT_1受体可能通过激活转录因子NF-κB和AP-1 Less来刺激小胶质细胞，从而增强致热性细胞因子的产生。