TY - JOUR
T1 - Selenite cataracts
T2 - Activation of endoplasmic reticulum stress and loss of Nrf2/Keap1-dependent stress protection
AU - Palsamy, Periyasamy
AU - Bidasee, Keshore R.
AU - Shinohara, Toshimichi
N1 - Funding Information:
This work was supported in part by the RPB and EY0180172. We thank Janice A. Taylor and James R. Talaska of the Confocal Laser Scanning Microscope Core Facility at the University of Nebraska Medical Center for providing assistance with confocal microscopy and the Nebraska Research Initiative and the Eppley Cancer Center for their support of the Core Facility, and the UNMC DNA Sequencing Core Facility (supported by P20 RR016469 from the INBRE Program of the National Center for Research Resources ) for sequencing analysis.
PY - 2014/9
Y1 - 2014/9
N2 - 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 1-5days. All these lenses developed nuclear cataracts after 4-5days. Sodium selenite treated HLECs induced ER stress and activated the UPR leading to release of Ca2+ 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.
AB - 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 1-5days. All these lenses developed nuclear cataracts after 4-5days. Sodium selenite treated HLECs induced ER stress and activated the UPR leading to release of Ca2+ 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.
KW - Cataract
KW - ER stress
KW - Human lens epithelial cells
KW - Keap1 promoter demethylation
KW - Sodium selenite
KW - Unfolded protein response
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U2 - 10.1016/j.bbadis.2014.06.028
DO - 10.1016/j.bbadis.2014.06.028
M3 - Article
C2 - 24997453
AN - SCOPUS:84904411046
SN - 0925-4439
VL - 1842
SP - 1794
EP - 1805
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 9
ER -