Abstract
Exposure to stress plays a detrimental role in the pathogenesis of hypertension via neuroinflammation pathways. Microglial neuroinflammation in the rostral ventrolateral medulla (RVLM) exacerbates stress-induced hypertension (SIH) by increasing sympathetic hyperactivity. Mitochondria of microglia are the regulators of innate immune response. Sigma-1R (σ-1R) localizes to the mitochondria-associated membranes (MAMs) and regulates endoplasmic reticulum (ER) and mitochondria communication, in part through its chaperone activity. The present study aims to investigate the protective role of σ-1R on microglial-mediated neuroinflammation. Stress-induced hypertension (SIH) was induced in rats using electric foot shocks and intermittent noise. Arterial blood pressure (ABP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were measured to evaluate the sympathetic nervous system (SNS) activities. SKF10047 (100µM), an agonist of σ-1R, was administrated to rats, then σ-1R localization and MAM alterations were detected by immuno-electron microscopy. Mitochondrial calcium homeostasis was examined in primary microglia and/or BV-2 microglia cells. The effect of SKF10047 treatment on the mitochondrial respiratory function of cultured microglia was measured using a Seahorse Extracellular Flux Analyzer. Confocal microscopic images were performed to indicate mitochondrial dynamics. Stress reduces σ-1R's localization at the MAMs, leading to decreased ER-mitochondria contact and IP3R-GRP75-VDAC calcium transport complexes expression in the RVLM of rats. SKF10047 promotes the length and coverage of MAMs in the prorenin-treated microglia. Prorenin treatment increases mitoROS levels, and inhibits Ca2+ signalling between the two organelles, therefore negatively affects ATP production in BV2 cells, and these effects are reversed by SKF10047 treatment. We found mitochondrial hyperfusion and microglial M1 polarization in prorenin-treated microglia. SKF10047 suppresses microglial M1 polarization and RVLM neuroinflammation, subsequently ameliorates sympathetic hyperactivity in stress-induced hypertensive rats. Sigma-1 receptor activation suppresses microglia M1 polarization and neuroinflammation via regulating endoplasmic reticulum-mitochondria contact and mitochondrial functions in stress-induced hypertension rats.
Highlights
Exposure to stress plays a detrimental role in the pathogenesis of hypertension via noninflammatory pathways
We find that mitochondrial hyperfusion and M1 polarization in prorenin-treated microglia
The depletion of σ-1R alters mitochondrial homeostasis and leads to the pathogenesis of numerous neurodegenerative diseases [27,28,29]. Consistent with these observations, our present study aims to reveal the neuroprotective of σ-1R activation, which might suppress microglia M1 polarization via regulating mitochondriaassociated membranes (MAMs)-dependent Ca2+ dynamic and mitochondrial functions, and alleviating neuroinflammation in stress-induced hypertension
Summary
Exposure to stress plays a detrimental role in the pathogenesis of hypertension via noninflammatory pathways. Microglial neuroinflammation in the rostral ventrolateral medulla (RVLM) exacerbates stress-induced hypertension (SIH) by increasing sympathetic hyperactivity. 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 confirmed 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]. A cause-effect linkage between microglial neuroinflammation and sympatho-excitatory neurons sensitization in the RVLM has been proposed. Several studies highlighted that neuroinflammation at the RVLM foci perturbs the physiological activity of the sympathetic centre, sensitizes the RVLM neurons and resulting in sympathetic hyperactivity[10,11,12]. The pathophysiology of dysregulated sympathetic activity in aggravating hypertension inspires us to study how this process is initiated because it may serve as a rationale for therapeutic intervention
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