ArticleFree radical biology & medicine2014
Epigenetic modifications of Nrf2-mediated glutamate-cysteine ligase: implications for the development of diabetic retinopathy and the metabolic memory phenomenon associated with its continued progression.
Article in Free radical biology & medicine, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed, 99 citations in OpenAlex.
- Article
- Experimental Diabetic Retinopathy in Wistar Rats Induced by Streptozotocin: A Window into Retinal Disease Progression.International journal of molecular sciences · 2026Article
- Beyond hyperglycemia: histone modification-mediated epigenetic dysregulation in diabetic retinopathy and nephropathy.Diabetology & metabolic syndrome · 2026Review
- Article
- Hormonal metabolic burden in diabetic retinopathy: the diabetic retina as an endocrine-responsive target organ.Frontiers in endocrinology · 2026Review
- Metabolic reprogramming in diabetic complications: mechanisms, pathologies, and molecular evidence from multi-organ studies.Frontiers in immunology · 2026Review
- USP16 S-nitrosylation aggravates coronary microembolization-induced myocardial injury via repressing KDM1A-mediated glutathione homeostasis.Nature communications · 2025Article
- N-acetyl-l-cysteine ethyl ester (NACET) induces the transcription factor NRF2 and prevents retinal aging and diabetic retinopathy.Redox biology · 2025Article
- Aloesin activates Nrf2 signaling to attenuate obesity-associated oxidative stress and hepatic steatosis in high-fat diet-fed rats.Scientific reports · 2025Article
- Review
- Retinal Gatekeepers: Molecular Mechanism and Therapeutic Role of Cysteine and Selenocysteine.Biomolecules · 2025Review
- Epigenetic Mechanisms Governing Nrf2 Expression and Its Role in Ferroptosis.Biomedicines · 2025Review
- Targeting oxidative stress in diabetic retinopathy: mechanisms, pathology, and novel treatment approaches.Frontiers in immunology · 2025Review
- Long noncoding RNAs and metabolic memory associated with continued progression of diabetic retinopathy.Journal of diabetes · 2024Article
- Article
- Article
- An update on chronic complications of diabetes mellitus: from molecular mechanisms to therapeutic strategies with a focus on metabolic memory.Molecular medicine (Cambridge, Mass.) · 2024Review
- Phloretamide Protects against Diabetic Kidney Damage and Dysfunction in Diabetic Rats by Attenuating Hyperglycemia and Hyperlipidemia, Suppressing NF-κβ, and Upregulating Nrf2.Pharmaceutics · 2024Article
- Oxidative Stress and Its Regulation in Diabetic Retinopathy.Antioxidants (Basel, Switzerland) · 2023Review
- Roles of Histone Acetyltransferases and Deacetylases in the Retinal Development and Diseases.Molecular neurobiology · 2023Review
9 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Diabetes increases oxidative stress in the retina and decreases the levels of the intracellular antioxidant glutathione (GSH). The transcriptional factor Nrf2 regulates the expression of Gclc, the enzyme important in the biosynthesis of GSH, and in diabetes the binding of Nrf2 at the antioxidant response element region 4 (ARE4) is decreased. Our aim was to investigate the role of epigenetic modifications in the decreased Nrf2 binding at Gclc-ARE4 in the development of diabetic retinopathy and in the metabolic memory associated with its continued progression. The effect of hyperglycemia on H3K4 methylation in Nrf2 binding at Gclc-ARE4 was investigated by chromatin immunoprecipitation in the rat retina and was confirmed in retinal endothelial cells in which histone demethylase (LSD1) was manipulated. The role of histone methylation at Gclc-ARE4 in the metabolic memory was examined in rats maintained under poor control for 3 months followed by good control (GC) for 3 months. Although H3K4me2 at Gclc-ARE4 was increased in diabetes, H3K4me3 and H3K4me1 were decreased. LSD1 siRNA abrogated the glucose-induced decrease in H3K4me1 at Gclc-ARE4 and ameliorated decreases in Nrf2 binding at Gclc-ARE4 and Gclc transcripts. Reestablishment of GC failed to provide any benefits to histone methylation, and Nrf2 binding activity remained compromised. Thus, in diabetic retinopathy, histone methylation at Gclc-ARE4 plays an important role in regulating the Nrf2-Gclc-GSH cascade. Targeting histone methylation could help inhibit/slow down this blinding disease.
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Registered trials
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