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lüll Stimulation of transient receptor potential vanilloid 4 channel suppresses abnormal activation of microglia induced by lipopolysaccharide Konno M; Shirakawa H; Iida S; Sakimoto S; Matsutani I; Miyake T; Kageyama K; Nakagawa T; Shibasaki K; Kaneko SGlia 2012[May]; 60 (5): 761-70Microglia are intrinsic immune cells in the brain. In response to neurodegenerative events, excessively activated microglia change their shapes and release various cytokines leading to the pathogenesis of central nervous system (CNS) disease. Because the intracellular mechanisms of this process are still unclear, we have evaluated the functional roles of transient receptor potential vanilloid 4 (TRPV4) channel expressed in the microglia. Robust microglial activation after an injection of lipopolysaccharide (LPS) into the mouse cerebral ventricle was suppressed by concurrent administration of a selective TRPV4 agonist, 4alpha-phorbol 12,13-didecanoate (4alpha-PDD). When the mechanism was further investigated using cultured rat microglia intrinsically expressing functional TRPV4, release of tumor necrosis factor-alpha (TNF-alpha) and expression of galectin-3 were both increased by LPS. These increases were significantly suppressed by cotreatment with 4alpha-PDD, and the inhibitory effects of 4alpha-PDD were abolished by knockdown of TRPV4 or TRPV4 antagonists. The amplitude of voltage-dependent K(+) current, which is augmented during microglial activation, was also suppressed by 4alpha-PDD treatment. Opening of TRPV4 channels with 4alpha-PDD induced membrane depolarization mainly by increasing Na(+) influx. In addition, mimicking depolarization with a high-K(+) solution suppressed LPS-induced TNF-alpha release and galectin-3 upregulation. Both depolarizing treatments with 4alpha-PDD and high-K(+) solution decreased store-operated Ca(2+) influx caused by thapsigargin. These results suggest that depolarization in response to opening of the TRPV4 channel attenuates the driving force for extracellular Ca(2+) and suppresses microglial activation.|Animals[MESH]|Animals, Newborn[MESH]|Cells, Cultured[MESH]|Down-Regulation/*immunology[MESH]|Injections, Intraventricular[MESH]|Lipopolysaccharides/*administration & dosage/*antagonists & inhibitors[MESH]|Male[MESH]|Mice[MESH]|Mice, Inbred ICR[MESH]|Microglia/drug effects/*metabolism[MESH]|Phorbols/administration & dosage[MESH]|Rats[MESH]|Rats, Wistar[MESH]|TRPV Cation Channels/agonists/*biosynthesis/physiology[MESH]|Up-Regulation/*immunology[MESH] |