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Palsamy Periyasamy, Elanchezhian Rajan, Christian J. Madson, David W. Lynch, Masahiko Ayaki, Jiro Usukura, Toshimichi Shinohara; Diabetic Cataract: Endoplasmic Reticulum-Stress/Epigenetic Suppression of Nrf2-Keap1 Pathway for Many Antioxidant Enzymes. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5981.
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Early onset of age-related cataract (ARC) is often found in diabetic patients, whose glucose concentration fluctuates from hyper- to hypoglycemia. Endoplasmic reticulum stress responds to these glucose concentrations and activates protective signals through translational and transcriptional regulations, which is termed as unfolded protein response (UPR). There are increasing evidences available on the aging and cancer studies, which indicate that hypermethylation in the CpG islands of NF-E2-related factor 2 (Nrf2 gene), and its negative regulator, Kelch-like ECH-associated protein 1 (Keap1 gene), suppresses the expression of many antioxidant genes. During oxidative stress, Nrf2 escapes from Keap1-mediated repression and activates expression of antioxidant responsive element-dependent genes to preserve cellular redox homeostasis. Here, we aimed to investigate whether hypo- and hyperglycemia induces the UPR and also the antioxidant defense system failure during prolonged exposure to hypo- and hyperglycemia.
Human lens epithelial cells (LECs) and rat lenses were cultured in different glucose concentrations in DMEM at 1% oxygen. H2-DCFH-DA and EthD staining were used to detect ROS and cell death, respectively. Protein blot analyses were performed with Abs specific to UPR proteins. MS-PCR and DNA sequencing were used to identify the methylated DNA.
Activation of UPR in 0, 50, 100 mM glucose after 3 hrs was observed and was increased with incubation time, along with higher levels of ROS and cell death. Nrf2 and Keap1 were also upregulated in 0, 50, and 100 mM glucose but prolonged exposure decreased the levels of Nrf2 and Keap1. Fluctuations of glucose concentrations from 100 mM to 1 mM did not enhance the activation of the UPR. UPR specific proteins were predominantly localized in LECs of the rat lenses treated with no or high levels of glucose. Bisulfite DNA sequencing showed that the CpG island of Nrf2 and Keap1 promoters had methylated cytosines in more than 30 capsulotomy specimens of ARCs.
No or high glucose induces UPR and generates ROS. Eventually Nrf2 and Keap1 are suppressed by epigenetic modifications which ultimately lower the transcription of antioxidant genes and induce lens oxidation and cell death in LECs, perhaps in ARCs.
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