DB20-0375_Supplementary_tables.pdf (71.66 kB)
Download fileLong noncoding RNA MALAT1 and regulation of the antioxidant defense system in diabetic retinopathy
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posted on 2020-10-13, 15:19 authored by Ada AdminAda Admin, Rakesh Radhakrishnan, Renu A. KowluruRetina
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.