Diabetic retinopathy (DR) is a sight-threatening complication of both type-1 and type-2 diabetes. The recent success of treatments inhibiting the function of vascular endothelial growth factor (VEGF) demonstrates that specific targeting of a growth factor responsible for vascular permeability and growth is an effective means of treating DRtargets involved in the control of retinal vascular function. However, additional treatment options and preventative measures are still needed and these require a greater understanding of the pathological mechanisms leading to the disturbance of retinal tissue homeostasis in DR. Although severe DR can be treated as a vascular disease, abundant data suggests that inflammation is also occurring in the diabetic retina.Thus, anti-inflammatory therapies may also be useful for treatment and prevention of DR. Herein, the evidence for altered expression of angiogenic factors and cytokines in DR is reviewed and possible mechanisms by which the expression of VEGF and cytokines may be increased in the diabetic retina are examined. In addition, the potential role for microglial activation in diabetic retinal neuroinflammation is explored.
METHODS.Retinal tissues were retrieved from postmortem human eyes, including 19 individuals without diabetes, 20 with diabetes but without DR, and 20 with diabetes and DR, for lipidomic study. In a parallel study, serum samples from 28 American Indians with type 2 diabetes from the Gila River Indian Community, including 12 without DR, 7 with mild nonproliferative DR (NPDR), and 9 with moderate NPDR, were selected. A mass-spectrometry-based lipidomic platform was used to measure serum and tissue lipids.
RESULTS.In the postmortem retinas, we found a graded decrease of long-chain acylcarnitines and longer-chain fatty acid ester of hydroxyl fatty acids, diacylglycerols, triacylglycerols, phosphatidylcholines, and ceramide(NS) in central retina from individuals with no diabetes to those with diabetes with DR. The American Indians' sera also exhibited a graded decrease in circulating long-chain acylcarnitines and a graded increase in the intermediate-length saturated and monounsaturated triacylglycerols from no DR to moderate NPDR.CONCLUSION. These findings suggest diminished synthesis of complex lipids and impaired mitochondrial β-oxidation of fatty acids in retinal DR, with parallel changes in circulating lipids. TRIAL REGISTRATION. ClinicalTrials.gov NCT00340678.
Retinal detachment (RD) disrupts the nutritional support and oxygen delivery to photoreceptors (PRs), ultimately causing cell death. High-mobility group box 1 (HMGB1) can serve as an extracellular alarmin when released from stressed cells. PRs release HMGB1 after RD. The purpose of this study was to investigate the relationship between HMGB1 and PR survival after RD. METHODS. Acute RD was created by injection of hyaluronic acid (1%) into the subretinal space in C57BL/6 mice and mice with a rhodopsin-Cre-mediated conditional knockout (cKO) of HMGB1 in rods (HMGB1 Rod). Immunofluorescence (IF) in retinal sections was used to localize HMGB1, rhodopsin, and Iba-1 proteins. Optical coherence tomography and electroretinography were used to quantify retinal thickness and function, respectively. The morphology of the retina was assessed by hematoxylin and eosin. RESULTS. HMGB1 protein was localized to the nuclei of all retinal neurons, including PRs, with cones staining more intensely than rods. HMGB1 protein was also found in the inner and outer segments of cones but not rods. Creation of RD caused a dramatic increase of HMGB1 protein IF in rods. cKO of HMGB1 in rods did not affect retinal structure or function. However, after RD, loss of rods and reduction in the thickness of the outer nuclear layer were significantly increased in the HMGB1 Rod retinas as compared to the control. Interestingly, depletion of HMGB1 in rods did not affect the activation and mobilization of microglia/macrophages normally seen after RD. CONCLUSIONS. Increased HMGB1 expression in stressed rods may represent an intrinsic mechanism regulating their survival after RD.
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