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

Abstract

Background Exposure to stress plays a detrimental role in the pathogenesis of hypertension via nonin ammatory pathways. Microglial neuroin ammation 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 mitochondriaassociated 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 neuroin ammation.Methods 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 MAMs alterations were detected by immuno-electron microscopy. Mitochondrial calcium homeostasis was examined in primary microglia and/or BV-2 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.Results Stress reduced σ-1R in the MAMs localization, 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 Ca 2+ signaling between the two organelles, therefore negatively affects ATP production in BV2 cells, and these effects are reversed by SKF10047 treatment. We nd that mitochondrial hyperfusion and M1 polarization in prorenin-treated microglia. SKF10047 suppresses microglial M1 phenotype and RVLM neuroin ammation, subsequently ameliorates sympathetic hyperactivity in stress-induced hypertensive rats. Conclusion Sigma-1 receptor activation suppresses microglia M1 polarization and neuroin ammation via regulating endoplasmic reticulum-mitochondria contact and mitochondrial functions in stress-induced hypertension rats.

Long-Lasting Nociplastic Pain Modulation by Repeated Administration of Sigma-1 Receptor Antagonist BD1063 in Fibromyalgia-like Mouse Models

“…The results obtained with pregabalin do not support a modulatory role of this compound in modulating glial reactivity in the spinal cord in fibromyalgia-like models. The difference between BD1063 and pregabalin could be related to the expression of their respective molecular targets, as α 2 δ 1 subunits have not been described in astrocytes and microglial cells; however, σ1R is expressed in glial cells, both in astrocytes [ 63 , 65 , 69 , 102 , 103 , 104 , 105 ] and microglial cells [ 70 , 106 , 107 , 108 , 109 , 110 , 111 ]. In this way, as reported in other models of pathological pain, such as chronic constriction injury, there is an upregulation of σ1R expression in spinal cord astrocytes, accompanied by overexpression of GFAP.…”

Inhibition of cGAS in Paraventricular Nucleus Attenuates Hypertensive Heart Injury Via Regulating Microglial Autophagy

“…The medium was changed every 2 days. When the cells reached 80% confluence, they were split with 0.25% trypsin and sub-cultured for further passages as our previous study [ 36 ].…”

Common methods in mitochondrial research (Review)

“…However, the direct measurement of glycolysis by EcAR is somewhat biased since the addition of glucose enhances glycolysis and oxidative phosphorylation. This will lead to increased mitochondrial acidification, causing the calculated amount of glycolysis to be high (147)(148)(149).…”