Abstract
Purpose :
Bromodomain 4 is an epigenetic regulator that is upregulated in the retina of diabetic mice and the blood of diabetics with retinopathy. Bromodomain 4 can acetylate histones, induce inflammation, and enhance oxidative stress. This can initiate retinal pathogenesis. However, it is not yet known if Bromodomain 4 impacts the onset of diabetic retinopathy. We hypothesized that Bromodomain 4 induces retinal pathogenesis and the onset of diabetic retinopathy.
Methods :
Bromodomain 4 expression in the retinas of non-diabetic and streptozotocin(STZ)-diabetic C57BL/6 mice was quantified using qPCR analysis. Levels of Bromodomain 4 was also quantified in peripheral blood mononuclear cells (PBMC) of nondiabetics and Type II diabetics: without retinopathy or with diabetic macular edema. Retinas of untreated or JQ1 (Bromodomain 4 inhibitor) treated, nondiabetic and STZ-diabetic mice was stained with 4-HNE (a product of lipid peroxidation) for microscopic analysis of oxidative stress in the retina. Alternatively, levels of reactive oxygen species were quantified in control and Bromodomain 4 silenced human Muller glia cultured in euglycemic and hyperglycemic conditions. Also, inflammatory proteins in retinal lysates of non-diabetic, untreated diabetic, and JQ1 treated diabetic mice were analyzed using a protein array. Finally, vascular cell death and profusion was examined in the retinal vasculature of nondiabetic and diabetic, untreated and JQ1 treated C57BL/6 mice to determine if Bromodomain 4 impacts retinal pathogenesis and the onset of diabetic retinopathy.
Results :
Bromodomain 4 was constitutively expressed in PBMC and retinas, and significantly increased in diabetic human PBMC and murine retinas. Diabetes-mediated oxidative stress was significantly decreased when Bromodomain 4 was inhibited in the retinas of JQ1 treated diabetic mice and JQ1 treated human Muller glia. Additionally, JQ1 treatment significantly decreased diabetes-mediated retinal inflammation. Finally, when Bromodomain 4 was inhibited in JQ1 treated diabetic mice, retinal vascular impairment was ablated.
Conclusions :
These results provide evidence that Bromodomain 4 enhances retinal inflammation, oxidative stress, and the onset of diabetic retinopathy. Future studies will focus on post-translational mechanisms and epigenetic regulation of Bromodomain 4, which leads to retinal pathogenesis in the diabetic retina.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.