背景:经典的肾素-血管紧张素系统(RAS)诱导器官损伤,而ACE2/Ang-(1-7)/MasR轴与它相对。然而,ACE2在大脑中的作用尚不清楚。我们研究了ACE2在大脑中的作用。方法我们使用雄性C57BL/6J(WT)小鼠,ACE2基因敲除(KO)小鼠,和MPTP诱导的小鼠。行为测试证实了成功的建模。我们评估了ACE2KO对RAS轴和PD指数的影响,包括ACE,ACE2,AT1,AT2,MasR,TH,α-syn,和Iba1。我们通过蛋白质印迹和免疫荧光研究了ACE2和MasR在小胶质细胞活化中的参与。GSE10867和GSE26532数据集用于分析AT1拮抗剂和体外PD模型对小胶质细胞的影响。结果行为测试显示MPTP小鼠表现出运动障碍,抑郁症,焦虑,SN和CPU中的炎症标记物增加,抗氧化能力降低。ACE2KO使这些症状恶化,并加剧炎症和氧化应激。LPS诱导的ACE2/MasR在BV2细胞中的活化通过调节小胶质细胞极化证明了抗炎和神经保护作用。拮抗剂通过炎症和ROS过程抑制小胶质细胞活化。结论RAS轴通过调节炎症和氧化应激来维持中枢神经系统的功能,提示神经疾病治疗的潜在目标。了解小胶质细胞RAS激活可以提供新的治疗策略。
BACKGROUND: The classic renin-angiotensin system (RAS) induces organ damage, while the ACE2/Ang-(1-7)/MasR axis opposes it. However, the role of ACE2 in the brain is unclear. We studied ACE2\'s role in the brain.
METHODS: We used male C57BL/6J (WT) mice, ACE2 knockout (KO) mice, and MPTP-induced mice. Behavioral tests confirmed successful modeling. We assessed the impact of ACE2 KO on the RAS axis and PD index, including ACE, ACE2, AT1, AT2, MasR, TH, α-syn, and Iba1. We investigated ACE2 and MasR\'s involvement in microglial activation via western blot and immunofluorescence. GSE10867 and GSE26532 datasets were used to analyze the effects of AT1 antagonists and in vitro PD models on microglia.
RESULTS: Behavioral tests revealed that MPTP mice displayed motor deficits, depression, anxiety, and increased inflammatory markers in the SN and CPU, with reduced antioxidant capacity. ACE2 KO worsened these symptoms and exacerbated inflammation and oxidative stress. LPS-induced ACE2/MasR activation in BV2 cells demonstrated anti-inflammatory and neuroprotective effects by modulating microglial polarization. Antagonists inhibited microglial activation via inflammation and ROS processes.
CONCLUSIONS: The RAS axis regulates inflammation and oxidative stress to maintain CNS function, suggesting potential targets for neurologic disease treatment. Understanding microglial RAS activation can offer new therapeutic strategies.