Immune complex formation in human diabetic retina enhances toxicity of oxidized LDL towards retinal capillary pericytes

Abstract

This article is available online at http://www.jlr.org Diabetic retinopathy (DR) remains a leading cause of vision loss in working-age adults. Early disease is characterized by vascular abnormalities, including pericyte loss, basement membrane thickening, microaneurysm formation, and capillary leakage ( 1, 2 ). Pericytes are critical to vascular integrity ( 3 ), and their loss is considered an initiating event in DR.Dyslipidemia has been implicated in DR, and associations between plasma lipoprotein profi les and disease severity have been observed in large cohort studies ( 4-6 ), but were not of suffi cient strength to defi ne risk for individuals. The term "dyslipidemia" may include qualitative as well as quantitative alterations in plasma lipoproteins. The qualitative abnormalities include modifi cation by oxidation, but oxidized LDL (ox-LDL) constitutes only a small fraction of total plasma LDL, ranging from 0.001% in healthy people to 5% in the presence of cardiovascular

The progress in understanding and treatment of diabetic retinopathy

“…Furthermore, modified LDL may become immunogenic. It has been suggested that oxidized-LDL-immune complexes are present in human diabetic retinas and that, in cultured retinal pericytes, immunecomplexed oxidized LDL is even more toxic than oxidized LDL alone (Fu et al, 2014).…”

“…Other factors causing pericyte death may involve lipid abnormalities. For example, oxidised LDL-immune complex is a potent inflammatory insult to induce pericyte apoptosis(Fu et al, 2014). PPARα, an important modulator of lipid metabolism, protected diabetic mice from retinal pericyte dropout.High glucose not only leads to the accumulation of AGEs and the concomitant activation of the receptor for AGEs, RAGE, but can also activate other biochemical pathways, such as the hexosamine pathway(Kandarakis et al, 2014;Nishikawa et al, 2000).…”

Lipids and Diabetic Retinopathy

“…[44][45][46] These modified particles are cytotoxic to all retinal cell types, including capillary cells in the BRB (thus creating a positive feedback process in which transient leakiness of the BRB leads to chronic damage). 40,41,[47][48][49][50] Thus, serum lipid profile may be less important, and weakening of the BRB may be a prerequisite for local lipoprotein-mediated damage.…”

Oxidized Low-Density Lipoprotein and the Incidence of Proliferative Diabetic Retinopathy and Clinically Significant Macular Edema Determined From Fundus Photographs

“…3 This may lead to the peroxidation of low-density lipoprotein (LDL), which has been hypothesized to cause the death of retinal vessel pericytes, endothelial cells, and retinal cells of Müller, resulting in exacerbation of diabetic retinopathy (DR). 4 …”

“…4 In our report, we examine relationships of serum ox-LDL level with the incidence of proliferative DR (PDR), the incidence of diabetic macular edema (DME), and the worsening of DR by 2 or more steps in participants with type 1 diabetes in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR).…”