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Suofu Qin, Anne P. McLaughlin, Gerald W. De Vries; Protection of RPE Cells from Oxidative Injury by 15-Deoxy-Δ12,14-Prostaglandin J2 by Augmenting GSH and Activating MAPK. Invest. Ophthalmol. Vis. Sci. 2006;47(11):5098-5105. doi: 10.1167/iovs.06-0318.
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purpose. The goal of this study was to identify the mechanisms by which 15-deoxy-Δ12,14-prostaglandin J2 (dPGJ2) protects RPE cells from oxidative injury.
methods. Cell viability was determined by MTT assay. Protein expression and activation of signaling molecules were detected by Western blot. Reduced glutathione (GSH) was determined by a colorimetric assay kit. PPARγ expression was knockdown by small interfering (si)RNA technique.
results. dPGJ2 protected ARPE19 cells from oxidative injury, whereas the synthetic PPARγ agonists AGN195037 and rosiglitazone had no effect. PPARγ knockdown also did not affect dPGJ2’s protective activity. dPGJ2 upregulated GSH synthesis via induction of glutamylcysteine ligase. GSH depletion sensitized cells to oxidative stress and completely reversed the protective effect of dPGJ2. dPGJ2 activated ERK, JNK, and p38; GSH induction by dPGJ2 depended partially on JNK and p38. In addition, dPGJ2 significantly extended hydrogen peroxide–induced activation of JNK and p38, but not of Akt. Inhibition of MEK, JNK, and p38 abolished dPGJ2’s protection of ARPE19 cells from oxidative injury, whereas inhibiting PI3K/Akt pathway failed to affect dPGJ2’s protective effect. Heme oxygenase-1 was strongly induced by dPGJ2 but was not associated with protection.
conclusions. Independent of its PPARγ activity, dPGJ2 protected cells from oxidative stress by elevating GSH and enhancing MAPK activation. Thus, dPGJ2 may delay the development of dry-type age-related macular degeneration.
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