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Intraretinal Leakage and Oxidation of LDL in Diabetic Retinopathy

¹From the Harold Hamm Oklahoma Diabetes Center and the Section of Endocrinology and Diabetes and the ²Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; the ³Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, Texas; the ⁴Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma; and the ⁵Veterans Affairs Medical Center, Oklahoma City, Oklahoma.

PURPOSE. The pathogenesis of diabetic retinopathy (DR) is not fully understood. Clinical studies suggest that dyslipidemia is associated with the initiation and progression of DR. However, no direct evidence supports this theory.

METHODS. Immunostaining of apolipoprotein B100 (ApoB100, a marker of low-density lipoprotein [LDL]), macrophages, and oxidized LDL was performed in retinal sections from four different groups of subjects: nondiabetic, type 2 diabetic without clinical retinopathy, diabetic with moderate nonproliferative diabetic retinopathy (NPDR), and diabetic with proliferative diabetic retinopathy (PDR). Apoptosis was characterized using the TUNEL assay. In addition, in cell culture studies using in vitro-modified LDL, the induction of apoptosis by heavily oxidized-glycated LDL (HOG-LDL) in human retinal capillary pericytes (HRCPs) was assessed.

RESULTS. Intraretinal immunofluorescence of ApoB100 increased with the severity of DR. Macrophages were prominent only in sections from diabetic patients with PDR. Merged images revealed that ApoB100 partially colocalized with macrophages. Intraretinal oxidized LDL was absent in nondiabetic subjects but present in all three diabetic groups, increasing with the severity of DR. TUNEL-positive cells were present in retinas from diabetic subjects but absent in those from nondiabetic subjects. In cell culture, HOG-LDL induced the activation of caspase, mitochondrial dysfunction, and apoptosis in HRCPs.

CONCLUSIONS. These findings suggest a potentially important role for extravasated, modified LDL in promoting DR by promoting apoptotic pericyte loss.

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				S. X Zhang, J. J Wang, A. Dashti, K. Wilson, M.-H. Zou, L. Szweda, J.-X. Ma, and T. J Lyons Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein J. Mol. Endocrinol., September 1, 2008; 41(3): 135 - 143. [Abstract] [Full Text] [PDF]