Abstract
The role of high mobility group box 1 (HMGB1) in acute diabetic retinal damage has been demonstrated. We recently reported that glycyrrhizin, a HMGB1 inhibitor, protected the diabetic retina against neuronal, vascular, and permeability changes. In this study, we wanted to investigate the role of exchange protein for cAMP 1 (Epac1) on HMGB1 and the actions of glycyrrhizin. Using endothelial cell specific knockout mice for Epac1, we made some mice diabetic using streptozotocin, and treated some with glycyrrhizin for up to 6 months. We measured permeability, neuronal, and vascular changes in the Epac1 floxed and knockout mice. We also investigated whether Epac1 and glycyrrhizin work synergistically to reduce the retinal inflammatory mediators, tumor necrosis factor alpha (TNFα) and interleukin-1-beta (IL1β), as well as sirtuin 1 (SIRT1) levels. Epac1 and glycyrrhizin reduced inflammatory mediators with synergistic actions. Glycyrrhizin also increased SIRT1 levels in the Epac1 mice. Overall, these studies demonstrate that glycyrrhizin and Epac1 can work together to protect the retina. Finally, glycyrrhizin may regulate HMGB1 through increased SIRT1 actions.
Highlights
Diabetic retinopathy remains the leading cause of vision loss in working age adults
We recently reported that glycyrrhizin inhibited high mobility group box 1 (HMGB1) in the diabetic retina through anti-inflammatory mechanism [15]
Since we have previously shown that Epac1 reduced HMGB1 in REC in vitro [7,10], we wanted to investigate whether Epac1 worked upstream of HMGB1 to protect the diabetic retina
Summary
Diabetic retinopathy remains the leading cause of vision loss in working age adults. Numerous drugs have been tested for treatment of diabetic retinopathy with some having success for proliferative disease or macular edema, yet, these have unwanted side effects. One potential upstream regulator of retinal inflammation is exchange protein for cAMP 1 (Epac). One potential upstream regulator of retinal inflammation is exchange protein for cAMP 1 (Epac1) Both Epac and Epac have been localized in the retina [6], are expressed by bovine and human retinal endothelial cells, and shown to play a role in leukostasis. We recently demonstrated that Epac is a potential key signaling protein in β-adrenergic receptor actions to protect the retina against leukostasis and inflammatory mediators [7]. We used diabetic Epac floxed and endothelial cell specific knockout KO mice alone or treated with glycyrrhizin to investigate whether Epac could inhibit HMGB1 to protect the diabetic retina, as well as whether Epac and glycyrrhizin work synergistically to protect the retinal against diabetes-induced neuronal, vascular, and permeability changes
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