ACE2 在帕金森病小胶质细胞激活中对 RAS 轴的作用。

The role of ACE2 in RAS axis on microglia activation in Parkinson's disease.

机构信息

Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng 475004, China; Institute of Neurourology and Urodynamics, Huaihe Hospital of Henan University, Kaifeng 475000, China.

Institute of Neurourology and Urodynamics, Huaihe Hospital of Henan University, Kaifeng 475000, China.

出版信息

Neuroscience. 2024 Aug 16;553:128-144. doi: 10.1016/j.neuroscience.2024.06.024. Epub 2024 Jul 8.

DOI:10.1016/j.neuroscience.2024.06.024

PMID:38986737

Abstract

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.

METHOD

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.

RESULT

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.

CONCLUSION

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.

摘要

背景

经典的肾素-血管紧张素系统（RAS）会引起器官损伤，而 ACE2/Ang-(1-7)/MasR 轴则与之相反。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 敲除（KO）小鼠和 MPTP 诱导的小鼠。行为测试证实了模型的成功建立。我们评估了 ACE2 KO 对 RAS 轴和 PD 指标的影响，包括 ACE、ACE2、AT1、AT2、MasR、TH、α-syn 和 Iba1。我们通过 Western blot 和免疫荧光研究了 ACE2 和 MasR 对小胶质细胞激活的参与。使用 GSE10867 和 GSE26532 数据集分析了 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 小鼠表现出运动功能障碍、抑郁、焦虑和 SN 和 CPU 中炎症标志物增加，抗氧化能力降低。ACE2 KO 使这些症状恶化，并加剧炎症和氧化应激。LPS 诱导的 BV2 细胞中 ACE2/MasR 激活通过调节小胶质细胞极化表现出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激活。