The Early Pathogenesis of Diabetic Retinopathy and Its Attenuation by Sodium-Glucose Transporter 2 Inhibitors

Area of Science:

• Ophthalmology
• Endocrinology
• Pharmacology

Background:

• The early pathogenesis of diabetic retinopathy (DR) and its effective treatment strategies remain incompletely understood.
• Diabetic retinopathy is a leading cause of vision loss, necessitating research into its early mechanisms and preventative therapies.

Purpose of the Study:

• To investigate the early pathogenic changes in diabetic retinopathy using a mouse model.
• To evaluate the protective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on these early alterations.

Main Methods:

• Streptozotocin-induced diabetic mice were used to model early DR.
• Retinal vascular leakage, thickness, microglia morphology, and expression of key angiogenic factors (Ang-2, VEGF-A) were assessed.
• In vitro studies examined the direct effect of SGLT2 inhibitors on microglia activation.

Main Results:

• Diabetic mice exhibited increased retinal vascular leakage, thickness, microglia activation, angiopoietin-2 expression, and VEGF-A signaling within 2-4 weeks.
• SGLT2 inhibitors (luseogliflozin, ipragliflozin) demonstrated protective effects on retinal vasculature and thickness at doses without glucose-lowering effects.
• In vitro, SGLT2 inhibitors reduced lipopolysaccharide-induced microglia activation, suggesting a direct inhibitory action.

Conclusions:

• SGLT2 inhibitors may prevent early diabetic retinopathy by directly modulating microglia activation and mitigating key pathogenic pathways.
• These findings suggest a potential therapeutic role for SGLT2 inhibitors in the early prevention of diabetic retinopathy.