Hyperglycemia-induced miR182-5p drives glycolytic and angiogenic response in Proliferative Diabetic Retinopathy and RPE cells via depleting FoxO1.

PURPOSE: Diabetic Retinopathy (DR) is associated with metabolic dysfunction in cells such as retinal pigmented epithelium (RPE). Small molecular weight microRNAs can simultaneously regulate multiple gene products thus having pivotal roles in disease pathogenesis. Since miR182-5p is involved in regulating glycolysis and angiogenesis, two pathologic processes of DR, we investigated its status in DR eyes and in high glucose model in vitro. METHOD: ology: Total RNA was extracted from vitreous humor of PDR (n = 48) and macular hole (n = 22) subjects followed by quantification of miR182-5p and its target genes. ARPE-19 cells, cultured in DMEM under differential glucose conditions (5 mM and 25 mM) were used for metabolic and biochemical assays. Cells were transfected with miRNA182 mimic or antagomir to evaluate the gain and loss of function effects. RESULTS: PDR patient eyes had high levels of miR182-5p levels (p < 0.05). RPE cells under high glucose stress elevated miR182-5p expression with altered glycolytic pathway drivers such as HK2, PFKP and PKM2 over extended durations. Additionally, RPE cells under high glucose conditions exhibited reduced FoxO1 and enhanced Akt activation. RPE cells transfected with miR182-5p mimic phenocopied the enhanced basal and compensatory glycolytic rates observed under high glucose conditions with increased VEGF secretion. Conversely, inhibiting miR182-5p reduced Akt activation, glycolytic pathway proteins, and VEGF while stabilizing FoxO1. CONCLUSION: Glycolysis-associated proteins downstream of the FoxO1-Akt axis were regulated by miR182-5p. Further, miR182-5p increased expression of VEGFR2 and VEGF levels, likely via inhibition of ZNF24. Thus, the FoxO1-Akt-glycolysis/VEGF pathway driving metabolic dysfunction with concurrent angiogenic signaling in PDR may be potentially targeted for treatment via miR182-5p modulation.

Toxic posterior segment syndrome with retinal vasculitis likely caused by intraocular cotton fiber after vitreoretinal surgery - a case report.

BACKGROUND: Intraocular inflammation is common after anterior or posterior segment surgery. They typically manifest either as non-infectious inflammation of the anterior or posterior segment, known as toxic anterior or posterior segment syndrome (TPSS), or as sterile or infective endophthalmitis. In this report, we describe a rare case of TPSS following vitreoretinal surgery, presenting as hemorrhagic retinal vasculitis. CASE PRESENTATION: A 58-year-old male diagnosed with a left eye acute rhegmatogenous retinal detachment underwent an uneventful primary pars plana vitrectomy with silicone oil endotamponade on the same day of presentation. At presentation, there were no signs of intraocular inflammation, and his visual acuity in the affected eye was 20/200. RESULTS: The retina was well-attached with silicone oil in place on the first post-operative day. Along the inferior retinal periphery, a hemorrhagic occlusive vasculitis was observed. Clinical examination revealed retained intraocular cotton fiber along the inferotemporal quadrant over the retinal surface. In addition to the standard post-operative medications, a course of systemic steroids (40 mg per day of Prednisolone tablets) was started. At the end of the first post-operative week, clinical signs of hemorrhagic retinal vasculitis were beginning to resolve, and by the end of the fourth post-operative week, they had completely resolved. CONCLUSION: This report describes an unusual diagnosis of TPSS after vitreoretinal surgery, most likely due to the presence of an intraocular cotton fiber. This excessive inflammation of the posterior segment usually responds to a course of topical and systemic steroids.

Activated cGAS/STING signaling elicits endothelial cell senescence in early diabetic retinopathy.

Diabetic retinopathy (DR) is a leading cause of blindness in working-age adults and remains an important public health issue worldwide. Here we demonstrate that the expression of stimulator of interferon genes (STING) is increased in patients with DR and animal models of diabetic eye disease. STING has been previously shown to regulate cell senescence and inflammation, key contributors to the development and progression of DR. To investigate the mechanism whereby STING contributes to the pathogenesis of DR, diabetes was induced in STING-KO mice and STINGGT (loss-of-function mutation) mice, and molecular alterations and pathological changes in the retina were characterized. We report that retinal endothelial cell senescence, inflammation, and capillary degeneration were all inhibited in STING-KO diabetic mice; these observations were independently corroborated in STINGGT mice. These protective effects resulted from the reduction in TBK1, IRF3, and NF-κB phosphorylation in the absence of STING. Collectively, our results suggest that targeting STING may be an effective therapy for the early prevention and treatment of DR.