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Dongxu Fu, Mingyuan Wu, Jing Zhang, Shihe Yang, Mei Du, Kenneth Wilson, Timothy J. Lyons; Modified LDL Increases Endoplasmic Reticulum Stress And Retinal Injury In Diabetes Mellitus. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3549.
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Our previous studies have shown that extravasated and modified low density lipoprotein (LDL) is associated with pericyte loss, an early feature in diabetic retinopathy (DR). Our objective is to determine whether endoplasmic reticulum (ER) stress is associated with extravasated LDL-induced pericyte loss.
Highly oxidized glycated LDL (HOG-LDL) and native LDL (N-LDL) were exposed to human retinal capillary pericytes (HRCP) for 1-24h with or without 1h-pretreatment of the blockers of different pathways (PolyI, NAC, 4-PBA and CsA). Indices of oxidative stress, ER stress, autophagy, mitochondrial dysfunction and apoptosis were determined by Western Blot, Immunohistochemistry, RT-PCR and Flow Cytometry. In addition, immunohistochemistry was performed to detect ER stress markers in retina from two DR related animal models, streptozotocin (STZ)-induced diabetic hypercholesterolemic mice and HOG-LDL Intravitreous injection STZ-induced diabetic mice in vivo, and in human retinas from subjects with and without DR in ex-vivo.
Compared to N-LDL, HOG-LDL activated ER Stress via enhanced oxidative stress, and then resulted in apoptosis, autophagy, and mitochondrial dysfunction in HRCP. In animal studies, ER stress was enhanced in retina in DR-related animal models and were associated with retinal injury. ER stress was also enhanced in diabetic human retina, correlated with severity of the disease.
Our data suggested that modified LDL activates ER stress, resulting apoptotic pericyte loss in DR.
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