Extravascular modified lipoproteins: a role in the propagation of diabetic retinopathy in a mouse model of type 1 diabetes

Abstract

Aims/hypothesisWe aimed to determine whether plasma lipoproteins, after leakage into the retina and modification by glycation and oxidation, contribute to the development of diabetic retinopathy in a mouse model of type 1 diabetes.MethodsTo simulate permeation of plasma lipoproteins into retinal tissues, streptozotocin-induced mouse models of diabetes and non-diabetic mice were challenged with intravitreal injection of human ‘highly-oxidised glycated’ low-density lipoprotein (HOG-LDL), native- (N-) LDL, or the vehicle PBS. Retinal histology, electroretinography (ERG) and biochemical markers were assessed over the subsequent 14 days.ResultsIntravitreal administration of N-LDL and PBS had no effect on retinal structure or function in either diabetic or non-diabetic animals. In non-diabetic mice, HOG-LDL elicited a transient inflammatory response without altering retinal function, but in diabetic mice it caused severe, progressive retinal injury, with abnormal morphology, ERG changes, vascular leakage, vascular endothelial growth factor overexpression, gliosis, endoplasmic reticulum stress, and propensity to apoptosis.Conclusions/interpretationDiabetes confers susceptibility to retinal injury imposed by intravitreal injection of modified LDL. The data add to the existing evidence that extravasated, modified plasma lipoproteins contribute to the propagation of diabetic retinopathy. Intravitreal delivery of HOG-LDL simulates a stress known to be present, in addition to hyperglycaemia, in human diabetic retinopathy once blood-retinal barriers are compromised.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-4012-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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“…In an atheromatous plaque, the oxLDL concentration is much higher than in plasma and is associated with plaque instability [ 221 ]. It is similar in the diabetic retina [ 222 ]. However, there is a significant difference between the accumulation of modified lipoproteins in the arteries and the retina.…”

Apolipoprotein E2 and E3, but Not E4, Promote Retinal Pathologic Neovascularization

“…[7][8][9][10][11][12][13][14] Recently, Yu's group reported that diabetes confers susceptibility to retinal injury imposed by intravitreal injection of modified LDL. 15 These findings suggest that extravasated, modified plasma lipoproteins contribute to the propagation of DR.…”

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“…8 We have also shown that modified LDL is injurious to several retinal cell types, including RPEs. [9][10][11][12][13][14] We therefore hypothesized that extravasated, modified LDL might play an important role in DR development, 15 and might act, in part, by injuring not only the inner BRB but also the outer BRB. We also hypothesized that the protective effects of fenofibrate in DR include preservation of outer BRB integrity and reduction of vascular endothelial growth factor (VEGF) and inflammatory mediator expression.…”