Valproic acid suppresses Nrf2/Keap1 dependent antioxidant protection through induction of endoplasmic reticulum stress and Keap1 promoter DNA demethylation in human lens epithelial cells

Periyasamy Palsamy, Keshore R. Bidasee, Toshimichi Shinohara

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27 Citations (Scopus)

Abstract

Recent epidemiological studies confirm the prevalence of cataract in epileptic patients. Similarly, the drugs used to treat epilepsy also show the connection with increased cataract formation. In this present study, we investigated the suppression of Nrf2/Keap1 dependent antioxidant protection through induction of endoplasmic (ER) stress and Keap1 promoter DNA demethylation in human lens epithelial cells (HLECs) treated with valproic acid (VPA), an antiepileptic drug. 20mM VPA induces ER stress and activates the unfolded protein response (UPR) within 4h by activating the ER stress sensor proteins, such as PERK, IRE1α, and ATF6 in HLECs. Consequently, the integrated ER stress signals, such as eIF2α, ATF4, BiP, and CHOP are altered accordingly to induce ER-Ca2+ release, reactive oxygen species (ROS) overproduction, and cell death in HLECs treated with VPA. VPA also suppresses the Nrf2, catalase, and glutathione reductase expressions with significant increases in Keap1 protein. Bisulphite genomic DNA sequencing reveals the promoter DNA demethylation in the Keap1 promoter, which results in the overexpression of Keap1 mRNA and protein in HLECs treated with 20mM VPA. VPA also alters the expression profiles of passive DNA demethylation pathway enzymes such Dnmt1, Dnmt3a, Dnmt3b, and active DNA demethylation pathway enzyme, TET1 leading to DNA demethylation in the Keap1 promoter of HLECs. Overexpressed Keap1 decreases the Nrf2 level, thereby abolishing the Nrf2 dependent antioxidant protection. This might be responsible for lenticular proteins oxidation and cataract formation.

Original languageEnglish (US)
Pages (from-to)26-34
Number of pages9
JournalExperimental Eye Research
Volume121
DOIs
StatePublished - Apr 2014

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Endoplasmic Reticulum Stress
Valproic Acid
Lenses
Antioxidants
Epithelial Cells
DNA
Cataract
Unfolded Protein Response
Proteins
Glutathione Reductase
Enzymes
Heat-Shock Proteins
DNA Sequence Analysis
Anticonvulsants
Catalase
Epidemiologic Studies
Epilepsy
Reactive Oxygen Species
Cell Death
Messenger RNA

Keywords

  • Cataracts
  • DNA methylation
  • ER stress
  • Keap1 promoter demethylation
  • Nrf2
  • Unfolded protein response
  • Valproic acid

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

@article{1b1dd4820deb4a98a6cae590c987aeef,
title = "Valproic acid suppresses Nrf2/Keap1 dependent antioxidant protection through induction of endoplasmic reticulum stress and Keap1 promoter DNA demethylation in human lens epithelial cells",
abstract = "Recent epidemiological studies confirm the prevalence of cataract in epileptic patients. Similarly, the drugs used to treat epilepsy also show the connection with increased cataract formation. In this present study, we investigated the suppression of Nrf2/Keap1 dependent antioxidant protection through induction of endoplasmic (ER) stress and Keap1 promoter DNA demethylation in human lens epithelial cells (HLECs) treated with valproic acid (VPA), an antiepileptic drug. 20mM VPA induces ER stress and activates the unfolded protein response (UPR) within 4h by activating the ER stress sensor proteins, such as PERK, IRE1α, and ATF6 in HLECs. Consequently, the integrated ER stress signals, such as eIF2α, ATF4, BiP, and CHOP are altered accordingly to induce ER-Ca2+ release, reactive oxygen species (ROS) overproduction, and cell death in HLECs treated with VPA. VPA also suppresses the Nrf2, catalase, and glutathione reductase expressions with significant increases in Keap1 protein. Bisulphite genomic DNA sequencing reveals the promoter DNA demethylation in the Keap1 promoter, which results in the overexpression of Keap1 mRNA and protein in HLECs treated with 20mM VPA. VPA also alters the expression profiles of passive DNA demethylation pathway enzymes such Dnmt1, Dnmt3a, Dnmt3b, and active DNA demethylation pathway enzyme, TET1 leading to DNA demethylation in the Keap1 promoter of HLECs. Overexpressed Keap1 decreases the Nrf2 level, thereby abolishing the Nrf2 dependent antioxidant protection. This might be responsible for lenticular proteins oxidation and cataract formation.",
keywords = "Cataracts, DNA methylation, ER stress, Keap1 promoter demethylation, Nrf2, Unfolded protein response, Valproic acid",
author = "Periyasamy Palsamy and Bidasee, {Keshore R.} and Toshimichi Shinohara",
year = "2014",
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doi = "10.1016/j.exer.2014.01.021",
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T1 - Valproic acid suppresses Nrf2/Keap1 dependent antioxidant protection through induction of endoplasmic reticulum stress and Keap1 promoter DNA demethylation in human lens epithelial cells

AU - Palsamy, Periyasamy

AU - Bidasee, Keshore R.

AU - Shinohara, Toshimichi

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Y1 - 2014/4

N2 - Recent epidemiological studies confirm the prevalence of cataract in epileptic patients. Similarly, the drugs used to treat epilepsy also show the connection with increased cataract formation. In this present study, we investigated the suppression of Nrf2/Keap1 dependent antioxidant protection through induction of endoplasmic (ER) stress and Keap1 promoter DNA demethylation in human lens epithelial cells (HLECs) treated with valproic acid (VPA), an antiepileptic drug. 20mM VPA induces ER stress and activates the unfolded protein response (UPR) within 4h by activating the ER stress sensor proteins, such as PERK, IRE1α, and ATF6 in HLECs. Consequently, the integrated ER stress signals, such as eIF2α, ATF4, BiP, and CHOP are altered accordingly to induce ER-Ca2+ release, reactive oxygen species (ROS) overproduction, and cell death in HLECs treated with VPA. VPA also suppresses the Nrf2, catalase, and glutathione reductase expressions with significant increases in Keap1 protein. Bisulphite genomic DNA sequencing reveals the promoter DNA demethylation in the Keap1 promoter, which results in the overexpression of Keap1 mRNA and protein in HLECs treated with 20mM VPA. VPA also alters the expression profiles of passive DNA demethylation pathway enzymes such Dnmt1, Dnmt3a, Dnmt3b, and active DNA demethylation pathway enzyme, TET1 leading to DNA demethylation in the Keap1 promoter of HLECs. Overexpressed Keap1 decreases the Nrf2 level, thereby abolishing the Nrf2 dependent antioxidant protection. This might be responsible for lenticular proteins oxidation and cataract formation.

AB - Recent epidemiological studies confirm the prevalence of cataract in epileptic patients. Similarly, the drugs used to treat epilepsy also show the connection with increased cataract formation. In this present study, we investigated the suppression of Nrf2/Keap1 dependent antioxidant protection through induction of endoplasmic (ER) stress and Keap1 promoter DNA demethylation in human lens epithelial cells (HLECs) treated with valproic acid (VPA), an antiepileptic drug. 20mM VPA induces ER stress and activates the unfolded protein response (UPR) within 4h by activating the ER stress sensor proteins, such as PERK, IRE1α, and ATF6 in HLECs. Consequently, the integrated ER stress signals, such as eIF2α, ATF4, BiP, and CHOP are altered accordingly to induce ER-Ca2+ release, reactive oxygen species (ROS) overproduction, and cell death in HLECs treated with VPA. VPA also suppresses the Nrf2, catalase, and glutathione reductase expressions with significant increases in Keap1 protein. Bisulphite genomic DNA sequencing reveals the promoter DNA demethylation in the Keap1 promoter, which results in the overexpression of Keap1 mRNA and protein in HLECs treated with 20mM VPA. VPA also alters the expression profiles of passive DNA demethylation pathway enzymes such Dnmt1, Dnmt3a, Dnmt3b, and active DNA demethylation pathway enzyme, TET1 leading to DNA demethylation in the Keap1 promoter of HLECs. Overexpressed Keap1 decreases the Nrf2 level, thereby abolishing the Nrf2 dependent antioxidant protection. This might be responsible for lenticular proteins oxidation and cataract formation.

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KW - Unfolded protein response

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