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Yoo-Ri Chung, Jeong A Choi, Min Ji Kang, Jae-Young Koh, Young Hee Yoon; Endoplasmic reticulum stress is associated with pericyte loss at early retinopathy of streptozotocin-induced diabetic mice. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5839.
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The early event of diabetic retinopathy (DR) is the breakdown of blood-retinal barrier, leading to the increased permeability of retinal capillaries and followed secretion of inflammatory cytokines. The functional abnormalities and eventual loss of pericytes may play a critical role in this process. Endoplasmic reticulum (ER) stress is recently demonstrated to be involved in DR, especially in the early stage. We investigated the role of ER stress and zinc in streptozotocin (STZ) -induced diabetic mice and human retinal pericytes (HRP).
STZ-induced diabetic mice were used to examine the ER stress in diabetic retinopathy. Cultured HRP cells were treated with 500 ug/ml advanced glycation end products (AGE), 100 ug/ml modified low-density lipoprotein (mLDL), or 1 uM thapsigargin (TG), respectively. Clioquinol, an antifungal drug that acts as a zinc ionophore, was exposed to HRP with or without zinc supplementation. The level of ER stress was evaluated by western blot analysis.
In STZ-induced mice, loss of vascular integrity began to appear after 4 weeks, and the expression level of GRP78 and pPERK was increased at 3- and 4-week, then decreased by 6-week. In pericytes, GRP78 level was increased after treatment of 500 ug/ml AGE or 100 ug/ml mLDL, at 24 and 12 hours respectively, as well as TG-treated cells used as a positive control. The expression of GRP78 was also increased by clioquinol, but attenuated by zinc supplementation in TG, AGE or mLDL-exposed HRP.
We verified that ER stress markers were increased in STZ-induced diabetic mice and AGE or mLDL-exposed HRP, and that clioquinol attenuated this increased induction of ER stress with zinc supplementation. This suggests that clioquinol and zinc may attenuate the induction of ER stress, and further evaluation is needed for its possible protective effect in diabetic retinopathy.
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