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S. X. Zhang, J. Li, J. J. Wang; Endoplasmic Reticulum Stress Contributes to Retinal Inflammation and Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4804.
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Endoplasmic reticulum (ER) is the primary intracellular compartment responsible for protein folding and calcium homeostasis. ER stress, or accumulation of unfolded proteins in the ER, has been demonstrated as a causative factor in a wide range of pathological circumstances including neurodegenerative disorders, diabetes mellitus, ischemic injury, cancers, and inflammation. In the present study, we attempted to elucidate the role of ER stress in the pathogenesis of diabetic retinopathy.
Expression of ER stress markers and activation of the unfolded protein response (UPR) effectors were measured in several animal models of diabetes, including Akita, db/db, streptozotocin (STZ)-induced diabetic mice and oxygen-induced retinopathy (OIR). The effect of ER stress on retinal inflammation and tight junction damage was determined using tunicamycin, a commonly used ER stress inducer, and 4-phenyl butyric acid (4-PBA), a low molecular weight chemical chaperon, in the in vivo and in vitro experimental systems.
ER stress markers GRP78 and phospho-IRE1 were significantly up-regulated in the retinas from db/db, Akita, STZ-diabetic and OIR mice. Moreover, the effectors of PERK UPR branch, including phospho-elf2 and ATF-4 were markedly increased in diabetic and OIR retinas, in parallel with increased levels of cytokines (TNF-, VEGF, and ICAM-1), decreased expression of tight junction proteins (occludin and VE-cadherin), and vascular leakage. Periocular administration of tunicamycin in adult C57 mice resulted in NF-ΚB activation in the retina and a subsequent increase of TNF- and VEGF expression accompanied by tight junction damage, indicating a direct effect of ER stress on retinal inflammation. In cultured human retinal endothelial cells, chemical chaperon 4-PBA reduced the hypoxia- and tunicamycin-induced ER stress and significantly reversed hypoxia- and tunicamycin-induced TNF- and VEGF over-expression. Moreover, local or systemic administration of 4-PBA successfully ameliorated NF-ΚB activation and inflammation in the retina in diabetic and OIR animals.
These findings indicate that ER stress is implicated in retinal inflammation and contributes to the pathogenesis of diabetic retinopathy.
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