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Article |
B Translocation with Elevated Hydrostatic Pressure
1 The Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee, United States
2 Ophthalmology and Visual Sciences, Vanderbilt University Medical School, 1115 Light Hall, Nashviille, Tennessee, 37232, United States
* To whom correspondence should be addressed. E-mail: david.j.calkins{at}vanderbilt.edu.
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Abstract |
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PURPOSE. We investigated the contribution of the transient receptor potential vanilloid-1 receptor (TRPV1) and Ca2+ to microglial IL-6 and NF
B translocation with elevated hydrostatic pressure. METHODS. We first examined IL-6 co-localization with the microglia marker Iba-1 in the DBA/2 mouse model of glaucoma to establish relevance. We isolated microglia from rat retina and maintained them at ambient or elevated (+70 mmHG) hydrostatic pressure in vitro and used ELISA and immunocytochemistry to measure changes in IL-6 concentration and NFB translocation induced by the Ca2+ chelator EGTA, the broad-spectrum Ca2+ channel inhibitor ruthenium red, and the TRPV1 antagonist I-RTX. We applied the Ca2+ dye Fluo-4 AM to measure changes in intracellular Ca2+ at elevated pressure induced by I-RTX and comfirmed TRPV1 expression in microglia using PCR and immunocytochemistry. RESULTS. In DBA/2 retina, elevated IOP increased microglial IL-6 in the ganglion cell layer. Elevated hydrostatic pressure (24hrs.) increased microglial IL-6 release, cytosolic NFB, and NFB translocation in vitro. These effects were reduced substantially both by EGTA and ruthenium red. Antagonism of TRPV1 in microglia partially inhibited pressure-induced increases in IL-6 release and NFB translocation. Brief elevated pressure (1hr.) induced a significant increase in microglial intracellular Ca2+, which was partially attenuated by TRPV1 antagonism. CONCLUSIONS. Elevated pressure induces an influx of extracellular Ca2+ in retinal microglia that precedes activation of NFB and subsequent production and release of IL-6 and is at least partially dependent on the activation of TRPV1 and other ruthenium red-sensitive channels.
Key Words: glial cell, interleukin, calcium channels, nuclear factor kappa B, DBA/2, hydrostatic pressure
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