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2014 ; 121
(ä): 26-34
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Valproic acid suppresses Nrf2/Keap1 dependent antioxidant protection through
induction of endoplasmic reticulum stress and Keap1 promoter DNA demethylation in
human lens epithelial cells
#MMPMID24525405
Palsamy P
; Bidasee KR
; Shinohara T
Exp Eye Res
2014[Apr]; 121
(ä): 26-34
PMID24525405
show ga
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.
20 mM VPA induces ER stress and activates the unfolded protein response (UPR)
within 4 h by activating the ER stress sensor proteins, such as PERK, IRE1?, and
ATF6 in HLECs. Consequently, the integrated ER stress signals, such as eIF2?,
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 20 mM 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.