Promoter demethylation of Keap1 gene in human diabetic cataractous lenses
Abstract
Highlights: Black-Right-Pointing-Pointer We found significant Keap1 promoter demethylation in diabetic cataractous lenses. Black-Right-Pointing-Pointer Demethylation of Keap1 gene upregulated the expression of Keap1 mRNA and protein. Black-Right-Pointing-Pointer Elevated levels of Keap1 are known to decrease the levels of Nrf2. Black-Right-Pointing-Pointer Thereby, the levels of antioxidant enzymes are suppressed by decreased Nrf2 level. -- Abstract: Age-related cataracts (ARCs) are the major cause of visual impairments worldwide, and diabetic adults tend to have an earlier onset of ARCs. Although age is the strongest risk factor for cataracts, little is known how age plays a role in the development of ARCs. It is known that oxidative stress in the lens increases with age and more so in the lenses of diabetics. One of the central adaptive responses against the oxidative stresses is the activation of the nuclear transcriptional factor, NF-E2-related factor 2 (Nrf2), which then activates more than 20 different antioxidative enzymes. Kelch-like ECH associated protein 1 (Keap1) targets and binds to Nrf2 for proteosomal degradation. We hypothesized that hyperglycemia will lead to a dysfunction of the Nrf2-dependent antioxidative protection in the lens of diabetics. We studied the methylation status of the CpG islands in 15 clear and 21 diabetic cataractous lenses. Our resultsmore »
- Authors:
-
- Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE (United States)
- Shizuoka National Hospital, Saitama (Japan)
- Publication Date:
- OSTI Identifier:
- 22207930
- Resource Type:
- Journal Article
- Journal Name:
- Biochemical and Biophysical Research Communications
- Additional Journal Information:
- Journal Volume: 423; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; ANTIOXIDANTS; CALVES; CATARACTS; DEOXYCYTIDINE; DNA; DNA SEQUENCING; ECR HEATING; ENDOPLASMIC RETICULUM; ENZYMES; GENES; MESSENGER-RNA; OXIDATION; OXYGEN; PROMOTERS
Citation Formats
Palsamy, Periyasamy, Ayaki, Masahiko, Elanchezhian, Rajan, and Shinohara, Toshimichi. Promoter demethylation of Keap1 gene in human diabetic cataractous lenses. United States: N. p., 2012.
Web. doi:10.1016/J.BBRC.2012.05.164.
Palsamy, Periyasamy, Ayaki, Masahiko, Elanchezhian, Rajan, & Shinohara, Toshimichi. Promoter demethylation of Keap1 gene in human diabetic cataractous lenses. United States. https://doi.org/10.1016/J.BBRC.2012.05.164
Palsamy, Periyasamy, Ayaki, Masahiko, Elanchezhian, Rajan, and Shinohara, Toshimichi. 2012.
"Promoter demethylation of Keap1 gene in human diabetic cataractous lenses". United States. https://doi.org/10.1016/J.BBRC.2012.05.164.
@article{osti_22207930,
title = {Promoter demethylation of Keap1 gene in human diabetic cataractous lenses},
author = {Palsamy, Periyasamy and Ayaki, Masahiko and Elanchezhian, Rajan and Shinohara, Toshimichi},
abstractNote = {Highlights: Black-Right-Pointing-Pointer We found significant Keap1 promoter demethylation in diabetic cataractous lenses. Black-Right-Pointing-Pointer Demethylation of Keap1 gene upregulated the expression of Keap1 mRNA and protein. Black-Right-Pointing-Pointer Elevated levels of Keap1 are known to decrease the levels of Nrf2. Black-Right-Pointing-Pointer Thereby, the levels of antioxidant enzymes are suppressed by decreased Nrf2 level. -- Abstract: Age-related cataracts (ARCs) are the major cause of visual impairments worldwide, and diabetic adults tend to have an earlier onset of ARCs. Although age is the strongest risk factor for cataracts, little is known how age plays a role in the development of ARCs. It is known that oxidative stress in the lens increases with age and more so in the lenses of diabetics. One of the central adaptive responses against the oxidative stresses is the activation of the nuclear transcriptional factor, NF-E2-related factor 2 (Nrf2), which then activates more than 20 different antioxidative enzymes. Kelch-like ECH associated protein 1 (Keap1) targets and binds to Nrf2 for proteosomal degradation. We hypothesized that hyperglycemia will lead to a dysfunction of the Nrf2-dependent antioxidative protection in the lens of diabetics. We studied the methylation status of the CpG islands in 15 clear and 21 diabetic cataractous lenses. Our results showed significant levels of demethylated DNA in the Keap1 promoter in the cataractous lenses from diabetic patients. In contrast, highly methylated DNA was found in the clear lens and tumorized human lens epithelial cell (HLEC) lines (SRA01/04). HLECs treated with a demethylation agent, 5-aza-2 Prime deoxycytidine (5-Aza), had a 10-fold higher levels of Keap1 mRNA, 3-fold increased levels of Keap1 protein, produced higher levels of ROS, and increased cell death. Our results indicated that demethylation of the CpG islands in the Keap1 promoter will activate the expression of Keap1 protein, which then increases the targeting of Nrf2 for proteosomal degradation. Decreased Nrf2 activity represses the transcription of many antioxidant enzyme genes and alters the redox-balance towards lens oxidation. Thus, the failure of antioxidant protection due to demethylation of the CpG islands in the Keap1 promoter is linked to the diabetic cataracts and possibly ARCs.},
doi = {10.1016/J.BBRC.2012.05.164},
url = {https://www.osti.gov/biblio/22207930},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 3,
volume = 423,
place = {United States},
year = {Fri Jul 06 00:00:00 EDT 2012},
month = {Fri Jul 06 00:00:00 EDT 2012}
}