Abstract
BackgroundMicroglial mediated neuroinflammation in the rostral ventrolateral medulla (RVLM) plays roles in the etiology of stress-induced hypertension (SIH). It was reported that autophagy influenced inflammation via immunophenotypic switching of microglia. High-mobility group box 1 (HMGB1) acts as a regulator of autophagy and initiates the production of proinflammatory cytokines (PICs), but the underlying mechanisms remain unclear.MethodsThe stressed mice were subjected to intermittent electric foot shocks plus noises administered for 2 h twice daily for 15 consecutive days. In mice, blood pressure (BP) and renal sympathetic nerve activity (RSNA) were monitored by noninvasive tail-cuff method and platinum-iridium electrodes placed respectively. Microinjection of siRNA-HMGB1 (siHMGB1) into the RVLM of mice to study the effect of HMGB1 on microglia M1 activation was done. mRFP-GFP-tandem fluorescent LC3 (tf-LC3) vectors were transfected into the RVLM to evaluate the process of autolysosome formation/autophagy flux. The expression of RAB7, lysosomal-associated membrane protein 1 (LAMP1), and lysosomal pH change were used to evaluate lysosomal function in microglia. Mitophagy was identified by transmission electron microscopic observation or by checking LC3 and MitoTracker colocalization under a confocal microscope.ResultsWe showed chronic stress increased cytoplasmic translocations of HMGB1 and upregulation of its receptor RAGE expression in microglia. The mitochondria injury, oxidative stress, and M1 polarization were attenuated in the RVLM of stressed Cre-CX3CR1/RAGEfl/fl mice. The HMGB1/RAGE axis increased at the early stage of stress-induced mitophagy flux while impairing the late stages of mitophagy flux in microglia, as revealed by decreased GFP fluorescence quenching of GFP-RFP-LC3-II puncta and decreased colocalization of lysosomes with mitochondria. The expressions of RAB7 and LAMP1 were decreased in the stressed microglia, while knockout of RAGE reversed these effects and caused an increase in acidity of lysosomes. siHMGB1 in the RVLM resulted in BP lowering and RSNA decreasing in SIH mice. When the autophagy inducer, rapamycin, is used to facilitate the mitophagy flux, this treatment results in attenuated NF-κB activation and reduced PIC release in exogenous disulfide HMGB1 (ds-HMGB1)-stimulated microglia.ConclusionsCollectively, we demonstrated that inhibition of the HMGB1/RAGE axis activation led to increased stress-induced mitophagy flux, hence reducing the activity of microglia-mediated neuroinflammation and consequently reduced the sympathetic vasoconstriction drive in the RVLM.
Highlights
The etiology of hypertension is extremely complex, involving both a strong genetic predisposition and multifactorial in pathogeneses
We have previously reported that the activated MG are increased in the rostral ventrolateral medulla (RVLM) of stress-induced hypertension (SIH) rats, and the secretion of Tumor necrosis factor α (TNF-α), IL-1β, and other proinflammatory cytokines (PICs) by microglia-mediated response resulted in increased blood pressure (BP) [11]
Microglia-specific knockout Advanced glycation end products receptor (RAGE) attenuated M1 polarization and lowered mean arterial blood pressure (MAP) and sympathetic activities which were indicated by reduced in renal sympathetic nerve activity (RSNA) in vivo We further identified whether endogenous High-mobility group box 1 (HMGB1)/ RAGE axis was involved in the pathogenesis of SIH
Summary
The etiology of hypertension is extremely complex, involving both a strong genetic predisposition and multifactorial in pathogeneses. It has been demonstrated that the augmenting sympathetic activity underlies the pathogenesis in hypertension and other cardiovascular events [4]. Humans with borderline hypertension and/or prehypertensive rat models show an elevation in centrally mediated sympathetic activity and an augmented neuroinflammatory state [5]. Overactive brain local renin-angiotensin system (RAS), oxidative stress, and neuroinflammation in the brainstem cardioregulatory centers rostral ventrolateral medulla (RVLM) and other brain regions such as hypothalamic paraventricular nucleus (PVN) are the key factors in augmenting sympathetic activity [6, 7]. It has been well established that sympathetic excitation and increased blood pressure (BP) are resulted from elevated oxidative stress and inflammation in the PVN, which excite PVN neurons [8]. Microglial mediated neuroinflammation in the rostral ventrolateral medulla (RVLM) plays roles in the etiology of stress-induced hypertension (SIH). High-mobility group box 1 (HMGB1) acts as a regulator of autophagy and initiates the production of proinflammatory cytokines (PICs), but the underlying mechanisms remain unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
