Methylglyoxal induces endoplasmic reticulum stress and DNA demethylation in the Keap1 promoter of human lens epithelial cells and age-related cataracts

Periyasamy Palsamy, Keshore R. Bidasee, Masahiko Ayaki, Robert C. Augusteyn, Jefferson Y. Chan, Toshimichi Shinohara

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Age-related cataracts are a leading cause of blindness. Previously, we have demonstrated the association of the unfolded protein response with various cataractogenic stressors. However, DNA methylation alterations leading to suppression of lenticular antioxidant protection remains unclear. Here, we report the methylglyoxal-mediated sequential events responsible for Keap1 promoter DNA demethylation in human lens epithelial cells, because Keap1 is a negative regulatory protein that regulates the Nrf2 antioxidant protein. Methylglyoxal induces endoplasmic reticulum stress and activates the unfolded protein response leading to overproduction of reactive oxygen species before human lens epithelial cell death. Methylglyoxal also suppresses Nrf2 and DNA methyltransferases but activates the DNA demethylation pathway enzyme TET1. Bisulfite genomic DNA sequencing confirms the methylglyoxal-mediated Keap1 promoter DNA demethylation leading to overexpression of Keap1 mRNA and protein. Similarly, bisulfite genomic DNA sequencing shows that human clear lenses (n = 15) slowly lose 5-methylcytosine in the Keap1 promoter throughout life, at a rate of 1% per year. By contrast, diabetic cataractous lenses (n = 21) lose an average of 90% of the 5-methylcytosine regardless of age. Overexpressed Keap1 protein is responsible for decreasing Nrf2 by proteasomal degradation, thereby suppressing Nrf2-dependent stress protection. This study demonstrates for the first time the associations of unfolded protein response activation, Nrf2-dependent antioxidant system failure, and loss of Keap1 promoter methylation because of altered active and passive DNA demethylation pathway enzymes in human lens epithelial cells by methylglyoxal. As an outcome, the cellular redox balance is altered toward lens oxidation and cataract formation.

Original languageEnglish (US)
Pages (from-to)134-148
Number of pages15
JournalFree Radical Biology and Medicine
Volume72
DOIs
StatePublished - Jul 2014

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Pyruvaldehyde
Endoplasmic Reticulum Stress
Cataract
Lenses
Epithelial Cells
Unfolded Protein Response
DNA
5-Methylcytosine
Proteins
Antioxidants
DNA Sequence Analysis
Methyltransferases
DNA Methylation
Enzymes
Blindness
Methylation
Cell death
Oxidation-Reduction
Reactive Oxygen Species
Cell Death

Keywords

  • Cataracts
  • DNA methylation
  • ER stress
  • Free radicals
  • Keap1 promoter demethylation
  • Methylglyoxal
  • Nrf2-dependent antioxidant protection
  • Unfolded protein response

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Methylglyoxal induces endoplasmic reticulum stress and DNA demethylation in the Keap1 promoter of human lens epithelial cells and age-related cataracts. / Palsamy, Periyasamy; Bidasee, Keshore R.; Ayaki, Masahiko; Augusteyn, Robert C.; Chan, Jefferson Y.; Shinohara, Toshimichi.

In: Free Radical Biology and Medicine, Vol. 72, 07.2014, p. 134-148.

Research output: Contribution to journalArticle

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