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

我们研究了促炎转录因子[核因子-κB （NF-κB）和激活蛋白-1 (AP-1)]是否参与脑内血管紧张素II （ANG II）依赖性细胞因子的产生。有趣的是，我们发现单次体外注射脂多糖（LPS）对下丘脑、海马和小脑的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ANG型1 （AT_1）受体拮抗剂增强（而不是降低）大鼠海马和/或小脑中的NF-κB和AP-1活性。这些结果似乎不支持NF-κB和AP-1在ANG ii诱导的大鼠大脑中由LPS诱导的促炎细胞因子的产生增强中起关键作用的观点。然而，整个脑细胞只有一部分被脑巨噬细胞、小胶质细胞所占据。因此，我们进一步研究了ANG II及其受体是否通过影响NF-κB和AP-1的激活而参与lps诱导的小胶质细胞激活。为此，在原代培养的小胶质细胞中，研究了ATI受体拮抗剂氯沙坦对lps诱导的白细胞介素-1 （IL-1）和一氧化氮（NO）的产生、细胞形态学变化以及NF-κB和AP-1的激活的影响。我们的RT-PCR研究显示lps刺激的小胶质细胞有ATI受体mrna的显著表达。lps刺激的小胶质细胞表现出IL-1和亚硝酸盐浓度的增加，以及形态的改变。这些作用均被氯沙坦治疗所抑制。lps刺激的小胶质细胞中NF-κB和AP-1活性增强，氯沙坦明显抑制。ANG II的施用本身增强了lps诱导的亚硝酸盐浓度的增加。综上所述，这些结果表明，ANG II和AT_1受体刺激小胶质细胞可能通过激活转录因子NF-κB和AP-1 Less来促进热原细胞因子的产生

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