Abstract
Sigma 1 receptor (Sig1R), a putative molecular chaperone, has emerged as a novel therapeutic target for retinal degenerative disease. Earlier studies showed that activation of Sig1R via the high-affinity ligand (+)-pentazocine ((+)-PTZ) induced profound rescue of cone photoreceptor cells in the rd10 mouse model of retinitis pigmentosa; however the mechanism of rescue is unknown. Improved cone function in (+)-PTZ-treated mice was accompanied by reduced oxidative stress and normalization of levels of NRF2, a transcription factor that activates antioxidant response elements (AREs) of hundreds of cytoprotective genes. Here, we tested the hypothesis that modulation of NRF2 is central to Sig1R-mediated cone rescue. Activation of Sig1R in 661W cone cells using (+)-PTZ induced dose-dependent increases in NRF2-ARE binding activity and NRF2 gene/protein expression, whereas silencing Sig1R significantly decreased NRF2 protein levels and increased oxidative stress, although (+)-PTZ did not disrupt NRF2-KEAP1 binding. In vivo studies were conducted to investigate whether, in the absence of NRF2, activation of Sig1R rescues cones. (+)-PTZ was administered systemically for several weeks to rd10/nrf2 +/+ and rd10/nrf2 −/− mice. Through post-natal day 42, cone function was significant in rd10/nrf2 +/+ , but minimal in rd10/nrf2 −/− mice as indicated by electroretinographic recordings using natural noise stimuli, optical coherence tomography and retinal histological analyses. Immunodetection of cones was limited in (+)-PTZ-treated rd10/nrf2 −/− , though considerable in (+)-PTZ-treated rd10/nrf2 +/+ mice. The data suggest that Sig1R-mediated cone rescue requires NRF2 and provide evidence for a previously-unrecognized relationship between these proteins.
Original language | English (US) |
---|---|
Pages (from-to) | 604-616 |
Number of pages | 13 |
Journal | Free Radical Biology and Medicine |
Volume | 134 |
DOIs | |
State | Published - Apr 2019 |
Keywords
- NRF2-KEAP1
- NRF2-Neh luciferase assay
- Oxidative stress
- Retina
- Retinal neuroprotection
- Retinitis pigmentosa
- rd10 mouse
ASJC Scopus subject areas
- Biochemistry
- Physiology (medical)