Abstract
Purpose: Rod photoreceptors (rods) are the most numerous and metabolically active retinal cells, and are susceptible to metabolic stress in response to hyperglycemia. Yet the role of rods in diabetic retinopathy (DR) is controversial. This study aims to investigate if rods exposed to high glucose can trigger inflammatory and angiogenic responses in Müller glia (MG) and retinal microvascular endothelial cells (RMEC). Methods: The streptozocin-induced (STZ) model was used at 10 weeks of diabetes. Transcriptomic shifts in rods were analyzed by RNAseq. The mediators produced by rods were analyzed by multiplex ELISA. The effect of rod-produced mediators on RMEC permeability was assessed. Angiogenic responses of RMECs treated with rod-produced mediators were evaluated by proliferation, migration, and tube formation assays. The effect of rods on proangiogenic mediator production by RMECs and MG was evaluated by western blot. Results: Diabetes induced upregulation of transcripts for tnf (3-fold, P=0.006) and il1a (2.2-fold, P=0.001) in rods. Primary rod cultures treated with 25 mM D-glucose (high glucose) produced increased levels of VEGF (2.5-fold, p<0.05), TNF-α (2.4-fold, p<0.05), and IL-6 (2-fold, p<0.05) compared to rods treated with 5 mM D-glucose (normal glucose), or with 25 mM L-glucose (osmotic control). The mediators produced by rods treated with high glucose elicited increased RMEC proliferation (2.5 fold, p<0.001), RMEC migration (2-fold, p<0.001), and RMEC tube lengths (1.9-fold, p<0.001). The rod-produced mediators induced RMEC secretion of matrix metalloproteinase 2 (MMP-2) (8-fold increase, p<0.001) and of MMP-9 (5-fold increase, p<0.001). MG treated with rod-produced mediators increased their production of VEGF (4-fold, p<0.001) and of MMP-9 (5-fold, p<0.001). Conclusion: Rods in hyperglycemic conditions produce mediators that increase RMEC permeability, proliferation, migration, and branching and induce a proangiogenic secretory shift in RMEC and MG. Disclosure I.De la huerta: None. J.M.Poloway: None. V.Reddy: None. J.S.Penn: None. Funding National Institutes of Health (K08EY032620); International Retinal Research Foundation; Knights Templar Eye Foundation
Published Version
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