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

Abstract

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.

Increased (Pro)renin Receptor Expression in the Hypertensive Human Brain

“…It has further been shown that Ang II microinjection into the mouse RVLM results in increased BP (Sasaki and Dampney, 1990), an effect that is reversed by administration of an Ang II receptor antagonist (Ito and Sved, 1996;Dampney et al, 2002;Ito et al, 2002). The PRR is present in the RVLM of mice (Contrepas et al, 2009;Li et al, 2012;Xu et al, 2016) and rats (Hu et al, 2020). In addition, blocking the PRR with the peptide PRO20 (Li et al, 2015b) attenuates neuroinflammation and decreases BP and renal sympathetic nerve activity in these animals (Hu et al, 2020), establishing a major role for the RVLM-PRR in hypertension development.…”

“…The PRR is present in the RVLM of mice (Contrepas et al, 2009;Li et al, 2012;Xu et al, 2016) and rats (Hu et al, 2020). In addition, blocking the PRR with the peptide PRO20 (Li et al, 2015b) attenuates neuroinflammation and decreases BP and renal sympathetic nerve activity in these animals (Hu et al, 2020), establishing a major role for the RVLM-PRR in hypertension development. Our current study demonstrates that RVLM-PRR immunoreactivity in the HTN human is significantly higher than that in NTN subjects, indicating the potential clinical importance of the PRR in the RVLM in human hypertension development.…”

Sigma-1 Receptor Activation Suppresses Microglia M1 Polarization via Regulating Endoplasmic Reticulum–Mitochondria Contact and Mitochondrial Functions in Stress-induced Hypertension Rats

“…We recorded RSNA when the general procedures for acute experiments were ready, the RSNA recording method was adapted from our previous study [5]. In anesthetized rats (urethane 800 mg/kg and αchloralose 40 mg/kg ip), the right formal artery was catheterized for the recording of BP and HR using a Powerlab system (AD Instruments).…”

“…In SIH, multiple mechanisms have been proposed and sympathetic nervous system (SNS) hyperactivity has emerged as a major culprit [3]. Within the cardiovascular sympathetic regulatory centre, local enhanced reninangiotensin system (RAS) activity and augments SNS output, thereafter results in a sustained elevation of arterial blood pressure (BP) [4].This is also con rmed by several animal studies that demonstrate microinjection of prorenin (a precursor of RAS cascade) directly activates sympathetic hyperactivity whereas microinjection of prorenin antagonist attenuates the hypertensive effect [5,6]. Generally, SNS output elevates BP via direct stimulation of sympathetic nerve innervating cardiovascular organs, or via indirect enhancement of release of vasopressinergic hormones involved in salt, volume, and cardiovascular regulation [7].…”

“…It is well-established that damaged mitochondria generate cytosolic ROS by mitochondrial electron transport chain and NADPH oxidase (NOX). In our previous studies, we showed that mitochondrial-derived ROS initiates the neuroin ammation process by promoting NLRP3 in ammasome assembly [5]. On the contrary, selective ROS removal has been shown to effectively inhibit M1-derived neuroin ammation and sympathoexcitatory response [10].…”