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Long noncoding RNA MALAT1 and regulation of the antioxidant defense system in diabetic retinopathy

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posted on 13.10.2020 by Ada Admin, Rakesh Radhakrishnan, Renu A. Kowluru
Retina experiences increased oxidative stress in diabetes, and the transcriptional activity of Nrf2, critical in regulating many antioxidant genes, is decreased. 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 MALAT1 in regulation of Keap1-Nrf2-antioxidant defense in diabetic retinopathy. LncRNA MALAT1 expression (qRT-PCR, immunofluorescence, 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 MALAT1 levels by increasing Sp1 transcription factor binding at its promoter. Downregulation of LncRNA MALAT1 by its siRNA prevented glucose-induced increase in Keap1, 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 increase in LncRNA MALAT1 and its interactions with Keap1, and decrease in Nrf2-mediated antioxidant defense genes. Thus, LncRNA MALAT1, via Keap1-Nrf2, regulates antioxidant defense in diabetic retinopathy. Inhibition of LncRNA MALAT1 has potential to protect the retina from oxidative damage, and prevent/slow down diabetic retinopathy.

Funding

The study was supported in parts by grants from the National Institutes of Health (EY014370, EY017313 and EY022230) and from The Thomas Foundation to RAK, and an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology, Wayne State University.

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