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Jing Zhang, Mingyuan Wu, Dongxu Fu, Shihe Yang, Michael H. Elliott, Mei Du, Kenneth W. Wilson, Timothy J. Lyons; Acceleration Of Retinopathy By Intravitreal Injection Of Modified Low Density Lipoproteins In-STZ Diabetic Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5974.
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Clinical studies suggest that dyslipoproteinemia is associated with the initiation and progression of diabetic retinopathy (DR), but intra-retinal lipoprotein extravasation may be the key event. We previously showed that intra-retinal ApoB100 and oxidized LDL immunostaining increase with the severity of DR. However, the effects of modified LDL in the retina are poorly understood. Here, we modeled these effects using intra-vitreal injection of highly-oxidized glycated LDL (HOG-LDL), and assessing its effects on retina in STZ-diabetic mice. The data lead us to propose a new animal model for DR.
Diabetic mice were induced by STZ IP injection; age matched non-diabetic mice as control. Two months later, HOG-LDL, Native-LDL (N-LDL) or PBS was intravitreally injected. At 3, 7 and 14 days post-injection, full-field scotopic electroretinography (ERG: retinal function), H&E staining (histology), retinal vascular leakage of blood-retinal barrier (BRB) integrity were performed. In addition, western blot and immunohistochemistry were conducted to detect ER stress markers, angiogenesis factors, apoptosis, and retinal injury indices.
ERG: compared to N-LDL and PBS, HOG-LDL decreased a- and b-wave amplitudes at all time points, whereas in non-diabetic mice HOG-LDL had only transient effects at 7 days. Retinal histology: HOG-LDL induced time-dependent structural damage and inflammatory responses vs. PBS and N-LDL treated animals, while no significant effects were seen in non-diabetic mice. Retinal flat mount images and BRB quantification: HOG-LDL induced vascular permeability and increased leakage. Western blot and IHC data: HOG-LDL caused retinal injury, increasing GFAP expression, up-regulating VEGF, and activating ER stress in T1DM, but had no significant effects in non-diabetic mice.
Intravitreal injection of modified LDL simulates the presence of extravasated, modified, intra-retinal LDL in diabetes, and accelerates the progress of retinal injury in STZ mice.
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