title: Age-related cataracts: homocysteine coupled endoplasmic reticulum stress and suppression of Nrf2-dependent antioxidant protection.
abstract: To determine whether high levels of homocysteine (Hcy) induce endoplasmic reticulum (ER) stress with suppression of the nuclear factor-erythroid-2-related factor 2 (Nrf2)-dependent antioxidant protection in lens epithelial cells (LECs). ER stress was acutely induced by exposure of LECs to 100 μM Hcy without FCS and also by exposure to 5 mM Hcy with 10% FCS. After exposure to Hcy, significant changes were found in P-PERK, P-eIF2α, XBP1, Nrf2, and Keap1 within 24 h. The production of reactive oxygen species (ROS) was increased after Hcy exposure. The downstream enzymes of Nrf2 like, catalase, and glutathione reductase, were significantly decreased. These results suggested that the Hcy-induced ER stress suppressed the Nrf2-dependent antioxidant protection and simultaneously generated ROS which resulted in further oxidation and death of LECs. The loss of Nrf2 is mainly due to proteosomal degradation and m-calpain activation by the increased levels of cytoplasmic Ca(++). The caspases also play a role in the degradation of Nrf2. Our findings demonstrated that high levels of Hcy induce ER stress, chronic UPR, alter the levels of UPR specific proteins, increase the production of ROS, degrade Nrf2 and block the Nrf2-dependent antioxidant defense protection in LECs. Thus, the upregulation of ROS might exceed the Nrf2 dependent antioxidant defense protection in the LECs and result in the highly oxidized lenses and resulted in ARCs.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Rajan
authors.initials: R
authors.lastname: Elanchezhian
authors.forename: Periyasamy
authors.initials: P
authors.lastname: Palsamy
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Madson
authors.forename: David W
authors.initials: DW
authors.lastname: Lynch
authors.forename: Toshimichi
authors.initials: T
authors.lastname: Shinohara
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000375:Aging / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002386:Cataract / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002417:Cattle; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495637:Nfe2l2 protein, rat; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D006710:Homocysteine