ArticleThe Journal of biological chemistry2020
The stress response protein REDD1 promotes diabetes-induced oxidative stress in the retina by Keap1-independent Nrf2 degradation.
Article in The Journal of biological chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 82 citations in OpenAlex.
- Impact of a high inspired oxygen fraction on oxidative stress in pediatric patients: reassuring results based on a randomized trial.Medical gas research · 2025Trial
- Association of vitamin D3 and diabetic retinopathy in US adults: A cross-sectional study.Medicine · 2026Article
- Targeting of Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) Signaling Pathway in Age-Related Eye Diseases: Molecular Mechanisms and Opportunities for therapy.Journal of biochemical and molecular toxicology · 2026Review
- GSK3β promotes p53/Nrf2-dependent expression of the stress response protein REDD2 in retinal Müller glia exposed to hyperlipidemic conditions.Experimental eye research · 2026Article
- Esculeoside A attenuates aortic remodeling and early atherosclerosis-like changes, with protective effects strongly associated with Nrf2 activation in high-cholesterol-fed rats.Scientific reports · 2026Article
- Molecular stress and neurovascular injury in the diabetic retina.The Journal of clinical investigation · 2026Review
- Targeting endoplasmic reticulum stress in diabetic retinopathy: mechanistic insights and emerging therapies.Biological research · 2026Review
- Nrf2 Deficiency in Müller Cells Exacerbates Pathological Neovascularization in Ischemic Retinopathy.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- Portulaca oleracea-derived indoline amide ameliorates obesity and NAFLD in rats through Nrf2-dependent antioxidant and anti-inflammatory mechanisms.Scientific reports · 2025Article
- Aloesin activates Nrf2 signaling to attenuate obesity-associated oxidative stress and hepatic steatosis in high-fat diet-fed rats.Scientific reports · 2025Article
- Rapid proteasomal degradation of the stress response protein REDD2 is mediated by the E3 ligase HUWE1.Biochemical and biophysical research communications · 2025Article
- Cinnamic Acid: A Shield Against High-Fat-Diet-Induced Liver Injury-Exploring Nrf2's Protective Mechanisms.International journal of molecular sciences · 2025Article
- Oxidative Stress and Complement Activation in Aqueous Cells and Vitreous from Patient with Vitreoretinal Diseases: Comparison Between Diabetic ERM and PDR.Antioxidants (Basel, Switzerland) · 2025Article
- Pathophysiological Mechanisms of Diabetes-Induced Macrovascular and Microvascular Complications: The Role of Oxidative Stress.Medical sciences (Basel, Switzerland) · 2025Review
- DDIT4 participates in high glucose-induced fibroblast-like synoviocytes overactivation and cartilage injury by regulating glycolysis.Regenerative therapy · 2025Article
- Deletion of the stress response protein REDD1 prevents sodium iodate-induced RPE damage and photoreceptor loss.GeroScience · 2025Article
- REDD1 mediates HDM-induced nuclear-cytoplasmic translocation and release of IL-33 in airway epithelial cells by downregulating Nrf2.Respiratory research · 2025Article
- Identification and validation of integrated stress-response-related genes as biomarkers for age-related macular degeneration.Frontiers in molecular biosciences · 2025Article
- Research progress on Nrf2 intervention in the treatment of diabetic retinopathy.Frontiers in endocrinology · 2025Review
- A genome-wide scan of non-coding RNAs and enhancers for refractive error and myopia.Human genetics · 2025Article
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Authors and funding
6 authors at 1 institution in 1 country.
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Abstract
The transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2) plays a critical role in reducing oxidative stress by promoting the expression of antioxidant genes. Both individuals with diabetes and preclinical diabetes models exhibit evidence of a defect in retinal Nrf2 activation. We recently demonstrated that increased expression of the stress response protein regulated in development and DNA damage 1 (REDD1) is necessary for the development of oxidative stress in the retina of streptozotocin-induced diabetic mice. In the present study, we tested the hypothesis that REDD1 suppresses the retinal antioxidant response to diabetes by repressing Nrf2 function. We found that REDD1 ablation enhances Nrf2 DNA-binding activity in the retina and that the suppressive effect of diabetes on Nrf2 activity is absent in the retina of REDD1-deficient mice compared with WT. In human MIO-M1 Müller cell cultures, REDD1 deletion prevented oxidative stress in response to hyperglycemic conditions, and this protective effect required Nrf2. REDD1 suppressed Nrf2 stability by promoting its proteasomal degradation independently of Nrf2's interaction with Kelch-like ECH-associated protein 1 (Keap1), but REDD1-mediated Nrf2 degradation required glycogen synthase kinase 3 (GSK3) activity and Ser-351/Ser-356 of Nrf2. Diabetes diminished inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β) at Ser-9 in the retina of WT mice but not in REDD1-deficient mice. Pharmacological inhibition of GSK3 enhanced Nrf2 activity and prevented oxidative stress in the retina of diabetic mice. The findings support a model wherein hyperglycemia-induced REDD1 blunts the Nrf2 antioxidant response to diabetes by activating GSK3, which, in turn, phosphorylates Nrf2 to promote its degradation.
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