Astaxanthin restores defective autophagy in photoreceptor cells under high-glucose conditions

Abstract

Dysregulated autophagy in photoreceptor cells is a significant pathological feature of diabetic retinopathy that contributes to severe visual impairment. To date, however, no effective treatment has been established. Astaxanthin (AST), a potent antioxidant that regulates a key intracellular transcription factor Nrf2, has recently been recognized to effectively modulate autophagy in neuronal cells in addition to its anti-apoptotic properties. However, its effects on dysregulated autophagy in the retina remain poorly understood. Given the urgent need for novel treatments targeting autophagy in diabetic retinopathy, we explored the effects of AST on autophagy in mouse photoreceptor cells (661W cells) under high-glucose conditions. Markers such as LC3B-II, Beclin-1, and p62 were evaluated by western blotting to assess autophagic responses. Key signaling pathways known to regulate autophagy, including Nrf2-BNIP3-mTOR and Atg4, were evaluated using specific inhibitors, small interfering RNA, and activators to elucidate the underlying mechanisms of AST on autophagy. We demonstrated that autophagic activity was downregulated under high-glucose conditions and that AST treatment effectively restored this activity. This restorative effects of AST on autophagy were attenuated by the Nrf2 inhibitor ML385, BNIP3 small interfering RNA, and mTOR activator MHY1485, indicating that AST promotes autophagy through the Nrf2-BNIP3-mTOR pathway. Additionally, the inhibition of Atg4 by NSC185058 diminished the effects of AST. Our findings demonstrate that AST restores defective autophagy in photoreceptor cells via the Nrf2-BNIP3-mTOR and Atg4 pathways, highlighting its potential as a therapeutic agent to prevent photoreceptor cell death in diabetic retinopathy.