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.
Highlights
Diabetic retinopathy remains a leading cause of new-onset blindness in adults [1], but its pathogenesis is not fully understood
We found that circulating immune complexes containing oxidised LDL predicted severe diabetic retinopathy many years later [13]
Modified LDL induced retinal inflammation, endoplasmic reticulum (ER) stress and pro-apoptosis in diabetic mice To understand the molecular pathology of modified LDL-induced retinal injury in diabetes, we explored alterations in protein markers for glial activation (GFAP), angiogenesis/vascular permeability (VEGF), ER stress (KDEL and p-eIF2α) and apoptosis
Summary
Diabetic retinopathy remains a leading cause of new-onset blindness in adults [1], but its pathogenesis is not fully understood. Plasma lipoproteins have been implicated, as supported by numerous clinical and epidemiological studies; see reviews [3,4,5] and some key studies [6,7,8,9,10,11,12,13,14]. Most of these studies focus on standard measures of circulating lipids and lipoproteins, and in general, they show associations between ‘dyslipidaemia’, for example elevated plasma LDL-cholesterol or apolipoprotein B (apoB), and the severity of diabetic retinopathy. Associations between plasma lipoproteins and diabetic retinopathy, statistically significant in population studies, are too weak to define individual risk or prognosis, as recently underlined in two detailed reports [14, 15]
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