Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8260309 | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | 2014 | 12 Pages |
Abstract
Cataract-induced by sodium selenite in suckling rats is one of the suitable animal models to study the basic mechanism of human cataract formation. The aim of this present investigation is to study the endoplasmic reticulum (ER) stress-mediated activation of unfolded protein response (UPR), overproduction of reactive oxygen species (ROS), and suppression of Nrf2/Keap1-dependent antioxidant protection through endoplasmic reticulum-associated degradation (ERAD) pathway and Keap1 promoter DNA demethylation in human lens epithelial cells (HLECs) treated with sodium selenite. Lenses enucleated from sodium selenite injected rats generated overproduction of ROS in lens epithelial cells and newly formed lens fiber cells resulting in massive lens epithelial cells death after 1-5Â days. All these lenses developed nuclear cataracts after 4-5Â days. Sodium selenite treated HLECs induced ER stress and activated the UPR leading to release of Ca2Â + from ER, ROS overproduction and finally HLECs death. Sodium selenite also activated the mRNA expressions of passive DNA demethylation pathway enzymes such as Dnmt1, Dnmt3a, and Dnmt3b, and active DNA demethylation pathway enzyme, Tet1 leading to DNA demethylation in the Keap1 promoter of HLECs. This demethylated Keap1 promoter results in overexpression of Keap1 mRNA and protein. Overexpression Keap1 protein suppresses the Nrf2 protein through ERAD leading to suppression of Nrf2/Keap1 dependent antioxidant protection in the HLECs treated with sodium selenite. As an outcome, the cellular redox status is altered towards lens oxidation and results in cataract formation.
Keywords
PDIDnmtATF6eIF2αimmunoglobulin heavy-chain binding proteinNQO1AE1GCLCGCLMRT-qPCREro1GSHPBSSRXN1TET1ER oxidoreductin 1nuclear factor-erythroid-2-related factor 2ERADHLECsNrf22′,7′-dichlorodihydrofluorescein diacetateBiPkeap1C/EBP-homologous proteinDNA methyltransferaseIRE1αPKR-like endoplasmic reticulum kinaseROSinositol-requiring enzyme 1αendoplasmic reticulum-associated degradationCHOPreal-time quantitative PCRhuman lens epithelial cellssulfiredoxin-1endoplasmic reticulumeukaryotic translation initiation factor 2αPhosphate buffered salineactivating transcription factor 6SERCAAnion exchanger 1protein disulfide isomeraseKelch-like ECH-associated protein 1PERKreduced glutathioneglutamate-cysteine ligase modifier subunitglutamate-cysteine ligase catalytic subunitQuinone reductaseglutathione reductaseReactive oxygen species
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Authors
Periyasamy Palsamy, Keshore R. Bidasee, Toshimichi Shinohara,