Microglia-Derived NLRP3 Activation Mediates the Pressor Effect of Prorenin in the Rostral Ventrolateral Medulla of Stress-Induced Hypertensive Rats

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 proreninstimulated 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.