title: Sigma 1 receptor stimulation protects against oxidative damage through suppression of the ER stress responses in the human lens.
abstract: Stimulation of sigma-1 receptors is reported to protect against oxidative stress. The present study uses cells and tissue from the human lens to elucidate the relationship between the sigma 1 receptor, ER stress and oxidative stress-induced damage. Exposure of the human lens cell line FHL124 to increasing concentrations of H(2)O(2) led to reduced cell viability and increased apoptosis. In response to 30 μM H(2)O(2), levels of the ER stress proteins BiP, ATF6 and pEIF2α were significantly increased within 4h of exposure. Expression of the sigma 1 receptor was markedly increased in response to H(2)O(2). Application of 10 and 30 μM (+)-pentazocine, a sigma 1 receptor agonist, significantly inhibited the H(2)O(2) induced cell death. (+)-Pentazocine also suppressed the oxidative stress induced reduction of pro-caspase 12 and suppressed the induction of the ER stress proteins BiP and EIF2α. When applied to cultured human lenses, (+)-pentazocine protected against apoptotic cell death, LDH release and against H(2)O(2) induced opacification. These data demonstrate that stimulation of the sigma 1 receptor provides significant protection from oxidative damage and is, therefore, a putative therapeutic approach to delay the onset of diseases that may be triggered by oxidative damage, including cataract formation.
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK. Lixin.Wang@AlconLabs.com
authors.forename: Lixin
authors.initials: L
authors.lastname: Wang
authors.forename: Julie A
authors.initials: JA
authors.lastname: Eldred
authors.forename: Peter
authors.initials: P
authors.lastname: Sidaway
authors.forename: Julie
authors.initials: J
authors.lastname: Sanderson
authors.forename: Andrew J O
authors.initials: AJ
authors.lastname: Smith
authors.forename: Richard P
authors.initials: RP
authors.lastname: Bowater
authors.forename: John R
authors.initials: JR
authors.lastname: Reddan
authors.forename: I Michael
authors.initials: IM
authors.lastname: Wormstone
mesh_terms: D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D020287:In Situ Nick-End Labeling; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007908:Lens, Crystalline / Q000378:metabolism*; D018384:Oxidative Stress; D010423:Pentazocine / Q000494:pharmacology; D017480:Receptors, sigma / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D002118:Calcium; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D010423:Pentazocine; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor