|Transcription factor Nrf2-mediated antioxidant defense system in the development of diabetic retinopathy.|
|PMID: 23633659 Owner: NLM Status: MEDLINE|
|PURPOSE: Increase in reactive oxygen species (ROS) is one of the major retinal metabolic abnormalities associated with the development of diabetic retinopathy. NF-E2-related factor 2 (Nrf2), a redox sensitive factor, provides cellular defenses against the cytotoxic ROS. In stress conditions, Nrf2 dissociates from its cytosolic inhibitor, Kelch like-ECH-associated protein 1 (Keap1), and moves to the nucleus to regulate the transcription of antioxidant genes including the catalytic subunit of glutamylcysteine ligase (GCLC), a rate-limiting reduced glutathione (GSH) biosynthesis enzyme. Our aim is to understand the role of Nrf2-Keap1-GCLC in the development of diabetic retinopathy.
METHODS: Effect of diabetes on Nrf2-Keap1-GCLC pathway, and subcellular localization of Nrf2 and its binding with Keap1 was investigated in the retina of streptozotocin-induced diabetic rats. The binding of Nrf2 at GCLC was quantified by chromatin immunoprecipitation technique. The results were confirmed in isolated retinal endothelial cells, and also in the retina from human donors with diabetic retinopathy.
RESULTS: Diabetes increased retinal Nrf2 and its binding with Keap1, but decreased DNA-binding activity of Nrf2 and also its binding at the promoter region of GCLC. Similar impairments in Nrf2-Keap1-GCLC were observed in the endothelial cells exposed to high glucose and in the retina from donors with diabetic retinopathy. In retinal endothelial cells, glucose-induced impairments in Nrf2-GCLC were prevented by Nrf2 inducer tBHQ and also by Keap1-siRNA.
CONCLUSIONS: Due to increased binding of Nrf2 with Keap1, its translocation to the nucleus is compromised contributing to the decreased GSH levels. Thus, regulation of Nrf2-Keap1 by pharmacological or molecular means could serve as a potential adjunct therapy to combat oxidative stress and inhibit the development of diabetic retinopathy.
|Qing Zhong; Manish Mishra; Renu A Kowluru|
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|Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2013-06-06|
|Title: Investigative ophthalmology & visual science Volume: 54 ISSN: 1552-5783 ISO Abbreviation: Invest. Ophthalmol. Vis. Sci. Publication Date: 2013 Jun|
|Created Date: 2013-06-07 Completed Date: 2013-08-14 Revised Date: 2013-12-03|
Medline Journal Info:
|Nlm Unique ID: 7703701 Medline TA: Invest Ophthalmol Vis Sci Country: United States|
|Languages: eng Pagination: 3941-8 Citation Subset: IM|
|APA/MLA Format Download EndNote Download BibTex|
Antioxidants / metabolism
Cell Nucleus / metabolism
Diabetes Mellitus, Experimental / metabolism*
Diabetic Retinopathy / metabolism*
Endothelium, Vascular / drug effects, metabolism
Fluorescent Antibody Technique, Indirect
Glutamate-Cysteine Ligase / metabolism*
Glutathione / metabolism
Hydroquinones / pharmacology
Intracellular Signaling Peptides and Proteins / metabolism*
NF-E2-Related Factor 2 / physiology*
Oxidative Stress / drug effects
RNA, Small Interfering / metabolism
Reactive Oxygen Species / metabolism
Real-Time Polymerase Chain Reaction
Retinal Vessels / cytology
Signal Transduction / physiology
|0/Antioxidants; 0/Hydroquinones; 0/Intracellular Signaling Peptides and Proteins; 0/KEAP1 protein, rat; 0/NF-E2-Related Factor 2; 0/Nfe2l2 protein, rat; 0/RNA, Small Interfering; 0/Reactive Oxygen Species; C12674942B/2-tert-butylhydroquinone; EC 188.8.131.52/Glutamate-Cysteine Ligase; EC 184.108.40.206./GCLC protein, rat; GAN16C9B8O/Glutathione|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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