Long Noncoding RNA <i>MALAT1</i> and Regulation of the Antioxidant Defense System in Diabetic Retinopathy.

Abstract

The retina experiences increased oxidative stress in diabetes, and the transcriptional activity of Nrf2, which is critical in regulating many antioxidant genes, is decreased. The nuclear movement/transcriptional activity of Nrf2 is mediated by its intracellular inhibitor Keap1, and retinal Keap1 levels are increased in diabetes. Gene expression is also regulated by long noncoding RNAs (LncRNAs). Our aim was to investigate the role of LncRNA <i>MALAT1</i> in the regulation of Keap1-Nrf2-antioxidant defense in diabetic retinopathy. LncRNA <i>MALAT1</i> expression (quantitative real-time PCR, immunofluorescence, and RNA sequencing), its interactions with Keap1 (FACS), Keap1-Nrf2 interactions, and transcription of the antioxidant response genes (immunofluorescence and nuclear RNA sequencing) were investigated in retinal endothelial cells exposed to high glucose. Glucose increased LncRNA <i>MALAT1</i> levels by increasing Sp1 transcription factor binding at its promoter. Downregulation of LncRNA <i>MALAT1</i> by its siRNA prevented glucose-induced increase in <i>Keap1</i> and facilitated Nrf2 nuclear translocation and antioxidant gene transcription. Retinal microvessels from streptozotocin-induced diabetic mice and human donors with diabetic retinopathy also presented similar increases in LncRNA <i>MALAT1</i> and its interactions with <i>Keap1</i> and decreases in Nrf2-mediated antioxidant defense genes. Thus, LncRNA <i>MALAT1</i>, via Keap1<i>-</i>Nrf2, regulates antioxidant defense in diabetic retinopathy. Inhibition of LncRNA <i>MALAT1</i> has potential to protect the retina from oxidative damage and to prevent or slow down diabetic retinopathy.