Microglia-Derived NLRP3 Activation Mediates the Pressor Effect of Prorenin in the Rostral Ventrolateral Medulla of Stress-Induced Hypertensive Rats
Microglia-Derived NLRP3 Activation Mediates the Pressor Effect of Prorenin in the Rostral Ventrolateral Medulla of Stress-Induced Hypertensive Rats
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DOI：
10.1007/s12264-020-00484-9
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发表时间：
2020-04-03
影响因子：
5.6
通讯作者：
Xia, Chunmei
中科院分区：
文献类型：
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作者：
Hu, Li;Zhang, Shutian;Xia, Chunmei
自主脑区域如延髓吻侧腹外侧（RVLM）内小胶质细胞激活和神经炎症的增加与应激性高血压（SIH）有关。Prorenin是脑肾素-血管紧张素系统（RAS）的一员，可以直接激活小胶质细胞。本研究旨在探讨prorenin对SIH大鼠RVLM小胶质细胞活化的影响。将大鼠置于间歇性脚电加噪声刺激下，每天2次，每次2小时，连续15天，监测平均动脉压（MAP）和肾交感神经活动（RSNA）。结果显示，MAP和RSNA被增强，这与促炎表型（M1）转换的增加是平行的。SIH大鼠RVLM中Prorenin及其受体（PRR）表达及NLR家族pyrin domain containing 3 （NLRP3）活化增加。此外，PLX5622（一种小胶质细胞耗损剂）、MCC950（一种NLRP3抑制剂）和/或PRO20 （a （Pro）肾素受体拮抗剂）在大鼠中具有降压作用。PLX5622可降低SIH大鼠RVLM中NLRP3的表达。Mito-tracker染色显示，在泌乳素刺激的小胶质细胞中，NLRP3从线粒体转移到细胞质。Prorenin增加ros触发的M1表型转换和NLRP3激活，MCC950降低M1极化。综上所述，RVLM中prorenin的上调可能通过激活小胶质细胞衍生的NLRP3炎性体参与SIH的发病机制。prorenin和小胶质细胞NLRP3之间的联系为应激相关性高血压的治疗提供了新的见解。
Increased microglial activation and neuroinflammation within autonomic brain regions such as the rostral ventrolateral medulla (RVLM) have been implicated in stress-induced hypertension (SIH). Prorenin, a member of the brain renin-angiotensin system (RAS), can directly activate microglia. The present study aimed to investigate the effects of prorenin on microglial activation in the RVLM of SIH rats. Rats were subjected to intermittent electric foot-shocks plus noise, this stress was administered for 2 h twice daily for 15 consecutive days, and mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) were monitored. The results showed that MAP and RSNA were augmented, and this paralleled increased pro-inflammatory phenotype (M1) switching. Prorenin and its receptor (PRR) expression and the NLR family pyrin domain containing 3 (NLRP3) activation were increased in RVLM of SIH rats. In addition, PLX5622 (a microglial depletion agent), MCC950 (a NLRP3 inhibitor), and/or PRO20 (a (Pro)renin receptor antagonist) had antihypertensive effects in the rats. The NLRP3 expression in the RVLM was decreased in SIH rats treated with PLX5622. Mito-tracker staining showed translocation of NLRP3 from mitochondria to the cytoplasm in prorenin-stimulated microglia. Prorenin increased the ROS-triggering M1 phenotype-switching and NLRP3 activation, while MCC950 decreased the M1 polarization. In conclusion, upregulated prorenin in the RVLM may be involved in the pathogenesis of SIH, mediated by activation of the microglia-derived NLRP3 inflammasome. The link between prorenin and NLRP3 in microglia provides insights for the treatment of stress-related hypertension.