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Sandra S Hammer, Delaney McFarland, Nina Bornemann, Cristiano P Vieira, George Abela, Maria B Grant, Julia Busik; Cholesterol crystals promote diabetic retinopathy (DR) pathology.. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1771a.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetes-induced downregulation of LXRα signaling results in elevated retinal cholesterol levels and increased inflammation. In turn, elevated free cholesterol levels promote the formation of cholesterol crystals (CC). In atherosclerotic disease, CC have been shown to increase inflammation, cause complement activation and cell death. The role of CC in the pathogenesis of DR remains unknown and represents the main focus of this study.
In vivo CC were imaged in 6-month-old control db/dm and db/db mice using Scanning Electron Microscopy and quantified by semiquantitative ranking score system. Retinal cholesterol levels were measured using liquid chromatography mass spectrometry. DR progression was assayed using acellular capillary formation. Bovine retinal endothelial cells (BREC) and APRE-19 cells were treated with CC (2mg/ml) for 24hrs or CC sequestering drug, alpha cyclodextrin (α-CD) (10nM), for 30mins. Quantitative Real Time PCR (qRTPCR) was used to assay reverse cholesterol transport (RCT) pathway activation (ABCA1, ABCG1), complement pathway (C5aR) involvement and inflammation (ICAM1, IL8, IL6, MCP1 and E selectin). Trypan blue exclusion assay was used to measure cell death.
Diabetes-induced downregulation of LXRα leads to increased retinal cholesterol (p<0.001), inflammation (p<0.001) and acellular inflammation (p<0.001). This elevation in retinal cholesterol and inflammation levels promoted the in vivo formation of CC (5±3 per field in diabetic vs. 0±0 in non-diabetic control mice). In vivo pharmacological activation of LXRα signaling reduced diabetes-induced cholesterol accumulation (p<0.01; n=4). Moreover, treatment with CC in BREC and ARPE19 increased expression of the complement component receptor C5aR (p=0.015; n=3), inflammation (ICAM1, IL8, IL6, MCP1 and E selectin; p<0.001; n=3) and cell death (p=0.008; n=3). Treatment with α-CD reduced CC-induced inflammation in retinal barrier cells (p<0.01; n=3).
Diabetes-induced elevated retinal cholesterol levels result in the formation of pro-inflammatory and cell death inducing CC. Treatment strategies to lower retinal cholesterol levels and prevent CC formation (LXRα activation, statins), or to dissolve CC (α-CD) can offer a promising and effective therapeutic solution for the management of DR progression.
This is a 2020 ARVO Annual Meeting abstract.
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