The present data suggest that hyperglycemia increases O-GlcNAcylation in DR and that O-GlcNAcylation of the p65 subunit of NF-κB is involved in hyperglycemia-induced NF-κB activation and RGC death in DR.

Background/Aims: The present study addresses the role of tonicity response element binding protein (TonEBP) in retinal ganglion cell (RGC) death in diabetic retinopathy and the impact of Aralia elata extract on the TonEBP/RGC interaction. Methods: Diabetes was induced in C57BL/6 mice by intraperitoneal injection of streptozotocin (STZ). Control mice received phosphate-buffered saline. After five injections of STZ or saline buffer, A. elata extract was administered by daily oral tube feeding for 7 weeks. All mice were killed at 2 months after the last injection of STZ or saline and the extent of cell death together with the protein expression levels of TonEBP, aldose reductase (AR) and nuclear factor-kappa B (NF-κB) were examined. Results: Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive signals were colocalized with TonEBP-immunoreactive RGCs. The apoptotic cell death of RGCs and the expression levels of TonEBP, AR and NF-κB were significantly increased in the retinas of diabetic mice compared with controls at 2 months after the induction of diabetes. However, these changes were effectively blocked by the administration of A. elata extract. Conclusions: These results indicate that A. elata prevents diabetes-induced RGC apoptosis and downregulates TonEBP expression. Therefore, A. elata extract may have therapeutic potential to prevent diabetes-induced retinal neurodegeneration in diabetic retinopathy.

O-GlcNAcylation of NF-κB is concerned in neuronal degeneration and that AE prevents diabetes-induced RGC apoptosis downregulation of NF-κB O-GlcNAcylation. Hence, O-GlcNAcylation may be a new object for the treatment of DR, and AE may have therapeutic possibility to prevent diabetes-induced neurodegeneration.

We investigated the role of nuclear factor of activated T cells 5 (NFAT5) under hyperosmotic conditions in human lens epithelial cells (HLECs). Hyperosmotic stress decreased the viability of human lens epithelial B-3 cells and significantly increased NFAT5 expression. Hyperosmotic stress-induced cell death occurred to a greater extent in NFAT5-knockout (KO) cells than in NFAT5 wild-type (NFAT5 WT) cells. Bcl-2 and Bcl-xl expression was down-regulated in NFAT5 WT cells and NFAT5 KO cells under hyperosmotic stress. Pre-treatment with a necroptosis inhibitor (necrostatin-1) significantly blocked hyperosmotic stress-induced death of NFAT5 KO cells, but not of NFAT5 WT cells. The phosphorylation levels of receptor-interacting protein kinase 1 (RIP1) and RIP3, which indicate the occurrence of necroptosis, were up-regulated in NFAT5 KO cells, suggesting that death of these cells is predominantly related to the necroptosis pathway. This finding is the first to report that necroptosis occurs when lens epithelial cells are exposed to hyperosmolar conditions, and that NFAT5 is involved in this process.

Steroid-induced cataracts (SIC) are defined as cataracts associated with the administration of corticosteroids. Long-term glucocorticoid treatment for inflammatory diseases reportedly increases the risk of SIC, and steroids can induce cataracts by disrupting ocular growth factor balance or homeostasis. In this study, we verified the effect of chondroitin sulfate proteoglycan 5 (CSPG5) using dexamethasone (dexa)-treated human lens epithelial (HLE-B3) cells and the lens epithelium from the anterior capsule of SIC patients obtained during cataract surgery. CSPG5 expression increased in the lens epithelium of SIC patients. The downregulation of CSPG5 suppressed the dexa-induced epithelial–mesenchymal transition (EMT)-related protein expression and motility in HLE-B3 cells. The disruption of the transcription factors EZH2 and B-Myb downregulated CSPG5, dexa-induced fibronectin expression, and cell migration in HLE-B3 cells, reaffirming that CSPG5 expression regulates EMT in lens epithelial cells. Taken together, these results indicate that the steroid-induced effects on lens epithelial cells are mediated via alterations in CSPG5 expression. Therefore, our study emphasizes the potential of CSPG5 as a therapeutic target for the prevention and treatment of SIC.