Vitamin D receptor activation regulates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: Role of renin-angiotensin system
Vitamin D receptor activation regulates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: Role of renin-angiotensin system
复制标题
维生素 D 受体激活调节自发性高血压大鼠和血管紧张素 II 暴露的小胶质细胞的小胶质细胞极化和氧化应激：肾素-血管紧张素系统的作用
DOI：
10.1016/j.redox.2019.101295
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发表时间：
2019-09-01
期刊：
影响因子：
11.4
通讯作者：
Jiang, Pei
中科院分区：
文献类型：
--
作者：
Cui, Changmeng;Xu, Pengfei;Jiang, Pei
高血压是神经退行性疾病的主要易感因素之一，其特征是周围和大脑中的肾素-血管紧张素系统（RAS）被激活。维生素D（VitD）是最近被认为是一种多效性激素，具有很强的神经保护作用。虽然多条证据表明VitD可以作用于RAS，但关于VitD和RAS在大脑中的串扰的证据有限。因此，本研究的目的是评估是否维生素D可以调节脑RAS触发自发性高血压大鼠（SHR）的脑神经保护作用。我们的数据表明，骨化三醇治疗诱导VDR表达和抑制SHR前额叶皮层神经元死亡。持续给予骨化三醇也抑制了小胶质细胞M1极化，但增强了M2极化，并伴随着促炎细胞因子表达的减少。然后我们进一步探讨了潜在的机制，并表明SHR表现出过度激活的经典RAS，血管紧张素II（Ang II）受体1型（AT 1）表达增加，血管紧张素转换酶（ACE）和Ang II的生产，而传统RAS的抵消臂，ACE 2/Ang（1-7）/MasR，在SHR脑中受损。骨化三醇对AT 1和ACE的抑制作用不显著，但显著降低Ang II的形成。值得注意的是，骨化三醇对ACE 2/Ang（1-7）/MasR轴具有显著影响，增加ACE 2、MasR和Ang（1-7）生成的表达。同时，骨化三醇还能改善SHR RAS下游的NADPH氧化酶（Nox）的过度激活，减轻氧化应激。在小胶质细胞（BV 2）中，我们进一步发现骨化三醇诱导ACE 2和MasR，而对ACE和AT 1没有显著影响。因此，骨化三醇也减弱了血管紧张素II诱导的Nox激活和ROS产生，并将小胶质细胞极化从M1表型转移到M2表型。然而，与特异性MasR拮抗剂A779共同治疗，废除了VitD的抗氧化和神经免疫调节作用。这些结果有力地表明ACE 2/Ang（1-7）/MasR通路参与了VitD在高血压脑中的神经保护机制。
Hypertension is one of the major predisposing factors for neurodegenerative disease characterized with activated renin-angiotensin system (RAS) in both periphery and brain. Vitamin D (VitD) is recently recognized as a pleiotropic hormone with strong neuroprotective properties. While multiple lines of evidence suggest that VitD can act on RAS, the evidence concerning the crosstalk between VitD and RAS in the brain is limited. Therefore, this study aims to evaluate whether VitD can modulate brain RAS to trigger neuroprotective actions in the brain of spontaneously hypertensive rats (SHR). Our data showed that calcitriol treatment induced VDR expression and inhibited neural death in the prefrontal cortex of SHR. Sustained calcitriol administration also inhibited microglia M1 polarization, but enhanced M2 polarization, accompanied with decreased expression of proinflammatory cytokines. We then further explored the potential mechanisms and showed that SHR exhibited overactivated classical RAS with increased expression of angiotensin II (Ang II) receptor type 1 (AT1), angiotensin converting enzyme (ACE) and Ang II production, whereas the counteracting arm of traditional RAS, ACE2/Ang(1-7)/MasR, was impaired in the SHR brain. Calcitriol nonsignificantly suppressed AT1 and ACE but markedly reduced Ang II formation. Intriguingly, calcitriol exerted pronouncedly impact on ACE2/Ang(1-7)/MasR axis with enhanced expression of ACE2, MasR and Ang(1-7) generation. Meanwhile, calcitriol ameliorated the overactivation of NADPH-oxidase (Nox), the downstream of RAS, in SHR, and also mitigated oxidative stress. In microglial (BV2) cells, we further found that calcitriol induced ACE2 and MasR with no significant impact on ACE and AT1. In accordance, calcitriol also attenuated Ang II-induced Nox activation and ROS production, and shifted the microglia polarization from M1 to M2 phenotype. However, co-treatment with A779, a specific MasR antagonist, abrogated the antioxidant and neuroimmune modulating actions of VitD. These findings strongly indicate the involvement of ACE2/Ang(1-7)/MasR pathway in the neuroprotective mechanisms of VitD in the hypertensive brain.