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

我们研究了促炎症转录因子[核因子-κB(核因子-κB)和激活蛋白-1(AP-1)]是否有助于脑内依赖血管紧张素II(Ang II)的细胞因子的产生。有趣的是，我们发现一个单一的静脉注射。注射脂多糖对下丘脑、海马区和小脑区的核因子-κB和AP-1活性无明显影响(下丘脑AP-1活性降低)。此外，血管紧张素转换酶抑制剂和血管紧张素转换酶1型受体拮抗剂均增强(而不是降低)脂多糖诱导的大鼠海马区和(或)小脑中核因子-κB和AP-1的活性。这些结果似乎不支持核因子-κB和AP-1在血管紧张素Ⅱ诱导的大鼠脑内促炎症细胞因子的产生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、小胶质细胞占据。因此，我们随后调查了…进一步研究血管紧张素Ⅱ及其受体是否通过影响核因子-κB和AP-1的激活而参与内毒素诱导的小胶质细胞活化。为此，我们观察了血管紧张素转换酶受体拮抗剂氯沙坦对内毒素诱导的小胶质细胞产生白介素1(IL-1)和一氧化氮(NO)的影响、细胞的形态变化以及对小胶质细胞原代培养中核因子κB和AP-1活化的影响。我们的RT-PCR研究表明，脂多糖刺激的小胶质细胞有明显的ATI受体的mRNAs表达。脂多糖刺激的小胶质细胞IL-1和亚硝酸盐浓度升高，形态发生改变。这些作用均可被氯沙坦抑制。内毒素刺激的小胶质细胞中，NF-κB和AP-1的活性增强，而氯沙坦对其活性有明显的抑制作用。应用血管紧张素转换酶II本身可增强内毒素诱导的亚硝酸盐浓度升高。总之，这些结果提示，Ang II和AT_1受体可能通过激活转录因子、核因子-κB和AP-1 Less来刺激小胶质细胞，从而促进致热细胞因子的产生

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