Search

Progression of diabetic retinopathy resists arrest even after institution of intensive glycemic control, suggesting a "metabolic memory" phenomenon, but the mechanism responsible for this phenomenon is still elusive. Gene expression and biological processes can also be regulated by long noncoding RNAs (LncRNAs), the RNAs with >200 nucleotides and no open reading frame for translation, and several LncRNAs are aberrantly expressed in diabetes. Our aim was to identify retinal LncRNAs that fail to reverse after termination of hyperglycemia. Microarray analysis was performed on retinal RNA from streptozotocin‐induced diabetic rats in poor glycemic control for 8 months, followed by in good glycemic control (blood glucose >400 mg/dL), or for 4 months, with four additional months of good glycemic control (blood glucose <150 mg/dL). Differentially expressed LncRNAs and mRNAs were identified through Volcano filtering, and their functions were predicted using gene ontology and pathway enrichment analyses. Compared with age‐matched normal rats, rats in continuous poor glycemic control had >1479 differentially expressed LncRNAs (710 downregulated, 769 upregulated), and among those, 511 common LncRNAs had similar expression in Diab and Rev groups (139 downregulated, 372 upregulated). Gene Ontology/pathway analysis identified limited LncRNAs in biological processes, but analysis based on biological processes/molecular function revealed >350 genes with similar expression in Diab and Rev groups; these genes were mainly associated with stress response, cell death, mitochondrial damage and cytokine production. Thus, identifying retinal LncRNAs and their gene targets that do not benefit from termination of hyperglycemia have potential to serve as therapeutic targets to slow down the progression of diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Aim: Hyperglycemia damages mitochondria and downregulates transcription of mtDNA-encoded genes and the long noncoding RNA LncCytB, causing mitochondrial genomic instability. The genes encoded by mtDNA are transcribed as large polycistronic transcripts, and the 5′ ends of precursor tRNAs are processed by mitochondrial-targeted ribonuclease P (MRPPs). Our aim was to investigate the role of MRPP1 in the downregulation of LncCytB in diabetic retinopathy. Methods: Using human retinal endothelial cells incubated in 20 mM D-glucose for 96 h, the gene expression and mitochondrial localization (immunofluorescence) of MRPP1 and the interaction between MRPP1 and LncCytB (determined by RNA-FISH and RNA immunoprecipitation) were quantified. The results were confirmed in retinal microvessels from streptozotocin-induced diabetic mice and from human donors with documented diabetic retinopathy. Results: Compared to normal glucose, high glucose decreased mRNA and mitochondrial localization of MRPP1 and its interaction with LncCytB. While MRPP1 overexpression prevented glucose-induced decrease in MRPP1–LncCytB interaction, LncCytB expression and mitochondrial damage (reduction in protective nucleoids in mtDNA), MRPP1-siRNA further worsened them. Similar results were obtained from retinal microvessels from diabetic mice and from human donors with diabetic retinopathy. Conclusions: Downregulation of MRPP1 in diabetes suppresses LncCytB transcription, resulting in mitochondrial functional and genomic instability, ultimately leading to the development of diabetic retinopathy. Thus, preventing MRPP1 downregulation has the potential to inhibit retinopathy and prevent the fear of vision loss in diabetic patients. [ABSTRACT FROM AUTHOR]