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 |
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Keywords
- NRF2-KEAP1
- NRF2-Neh luciferase assay
- Oxidative stress
- Retina
- Retinal neuroprotection
- Retinitis pigmentosa
- rd10 mouse
ASJC Scopus subject areas
- Biochemistry
- Physiology (medical)
Cite this
The molecular chaperone sigma 1 receptor mediates rescue of retinal cone photoreceptor cells via modulation of NRF2. / Wang, J.; Zhao, J.; Cui, X.; Mysona, B. A.; Navneet, S.; Saul, A.; Ahuja, M.; Lambert, N.; Gazaryan, I. G.; Thomas, B.; Bollinger, K. E.; Smith, S. B.
In: Free Radical Biology and Medicine, Vol. 134, 04.2019, p. 604-616.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The molecular chaperone sigma 1 receptor mediates rescue of retinal cone photoreceptor cells via modulation of NRF2
AU - Wang, J.
AU - Zhao, J.
AU - Cui, X.
AU - Mysona, B. A.
AU - Navneet, S.
AU - Saul, A.
AU - Ahuja, M.
AU - Lambert, N.
AU - Gazaryan, I. G.
AU - Thomas, B.
AU - Bollinger, K. E.
AU - Smith, S. B.
PY - 2019/4
Y1 - 2019/4
N2 - 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.
AB - 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.
KW - NRF2-KEAP1
KW - NRF2-Neh luciferase assay
KW - Oxidative stress
KW - Retina
KW - Retinal neuroprotection
KW - Retinitis pigmentosa
KW - rd10 mouse
UR - http://www.scopus.com/inward/record.url?scp=85061652524&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061652524&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2019.02.001
DO - 10.1016/j.freeradbiomed.2019.02.001
M3 - Article
C2 - 30743048
AN - SCOPUS:85061652524
VL - 134
SP - 604
EP - 616
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
SN - 0891-5849
ER -