Sigma 1 receptor stimulation protects against oxidative damage through suppression of the ER stress responses in the human lens

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 H2O2 led to reduced cell viability and increased apoptosis. In response to 30 μM H2O2, levels of the ER stress proteins BiP, ATF6 and pEIF2α were significantly increased within 4 h of exposure. Expression of the sigma 1 receptor was markedly increased in response to H2O2. Application of 10 and 30 μM (+)-pentazocine, a sigma 1 receptor agonist, significantly inhibited the H2O2 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 H2O2 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.

► Oxidative insult increases sigma 1 receptor expression and ER stress in human lens cells.
► Stimulation of the sigma 1 receptor provides significant protection against oxidative damage.
► Sigma 1 receptor agonist protection suppresses, but does not ablate the ER stress response.
► Sigma 1 receptor agonists can prevent ER stress induced apoptosis.