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Qing Zhong, Renu Kowluru; Role Of NF-E2-related Factor 2 In The Development And Progression Of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5412.
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Diabetes-induced oxidative stress is considered as a unified pathway resulting in the development of diabetic retinopathy. Our previous studies have shown that the level of the intracellular antioxidant glutathione (GSH) is decreased in the retina in diabetes, and the catalytic subunit of glutamylcysteine ligase (GCLC), an enzyme important in GSH synthesis, is compromised. GCLC transcript is regulated by transcription factor NF-E2-related factor 2 (Nrf2), and Nrf2 is implicated in the regulation of antioxidant genes through binding to the antioxidant-response element (ARE). The aim of this study is to investigate the role of Nrf2 in the development of diabetic retinopathy and in the metabolic memory associated with its continued progression.
Wistar rats, made diabetic by streptozotocin, were kept in either poor glycemic control for 6 months (PC, glycated hemoglobin, GHb >12%), or in good control for 6 months (GC, GHb ~6%), or in PC for 3 months followed by in GC for 3 months (Rev group). The gene and protein expressions of retinal Nrf2 and GCLC were measured by quantitative PCR and by western blot technique, respectively. DNA binding activity of Nrf2 was measured in the nuclear extract by an ELISA method in which the binding of the activated Nrf2 to the ARE oligonucleotide was quantified using anti-Nrf2 antibody. Nrf2 binding at the GCLC enhancer was detected by chromatin immunoprecipitation technique.
Retinal gene and protein expressions of Nrf2 were increased in diabetes, but Nrf2 DNA binding activity was decreased. In the same group, the gene transcripts of GCLC were subnormal, and the binding of Nrf2 at GCLC enhancer was also decreased. Reversal of hyperglycemia after 3 months of PC did not provide any benefit to these changes, and the binding of Nrf2 at GCLC continued to be subnormal compared to the values obtained from age-matched normal rats. The values obtained from rats in PC and Rev groups were not different from each other, but were significantly different from those obtained from GC group.
Although retinal Nrf2 expression is upregulated in diabetes, its DNA binding activity is compromised contributing to the decreased transcription of GCLC and subnormal levels of GSH. Attenuated Nrf2 transcriptional activity and its persistence after reversal of hyperglycemic insult suggest a major role of Nrf2 in the development, and also in continued progression, of diabetic retinopathy. Thus, Nrf2 inducers may serve as a potential strategy to combat oxidative stress experienced by the retina in diabetes, and inhibit the development of diabetic retinopathy.
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