Inhibition of HDAC3 Expression Alleviates High-Glucose-Induced Photoreceptor Cell Apoptosis and Oxidative Stress.

BACKGROUND: Diabetic retinopathy (DR), the most common ocular complication of diabetes mellitus, is a leading cause of blindness among the working-age population. Its pathogenesis is mainly related to blood-retinal barrier destruction, inflammation, retinal neuron damage, oxidative stress, and genetic immune factors. This study is aimed at elucidating the role and underlying mechanism of histone deacetylase 3 (HDAC3) in DR-associated retinal neuronal injury.

METHODS: In this study, the mouse model of diabetes was induced by intraperitoneal injection of streptozotocin (STZ) dissolved in sodium citrate buffer. At 4, 8, and 12 weeks, the thickness of the retinal and photoreceptor layers was observed by hematoxylin-eosin staining, and the expression of HDAC3 in the mouse retina was evaluated by immunohistochemical staining. In vitro, 661W cells were cultured under high-glucose conditions to mimic the diabetic environment. To investigate the role of HDAC3, its expression was inhibited using either the specific inhibitor RGFP966 or HDAC3-specific small interfering RNA (HDAC3-siRNA). Subsequently, the levels of oxidative stress and apoptosis were detected to analyze the mechanism by which HDAC3 influences photoreceptor damage.

RESULTS: With the prolongation of diabetes duration, the thickness of the retinal layer and photoreceptor cell layer becomes thinner, and the expression of HDAC3 in the retina increases. In vitro, HDAC3 expression, apoptosis, and oxidative stress were increased in 661W cells treated with high glucose. Critically, inhibition of HDAC3 using either RGFP966 or HDAC3-siRNA effectively attenuated the high-glucose-induced apoptosis and oxidative stress in these cells.

CONCLUSION: Our results suggest that HDAC3 is associated with apoptosis and oxidative stress of DR photoreceptors, and the inhibition of HDAC3 can reduce apoptosis and oxidative stress of DR photoreceptors. It is suggested that epigenetic therapy of HDAC3 inhibitors may have therapeutic value in the prevention and treatment of DR.