The molecular chaperone sigma 1 receptor mediates rescue of retinal cone photoreceptor cells via modulation of NRF2

Jing Wang, J. Zhao, X. Cui, Barbara A Mysona, S. Navneet, Alan B Saul, M. Ahuja, Nevin A Lambert, I. G. Gazaryan, Bobby Thomas, Kathryn Elizabeth Bollinger, Sylvia B Smith

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)604-616
Number of pages13
JournalFree Radical Biology and Medicine
Volume134
DOIs
StatePublished - Apr 1 2019

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Retinal Cone Photoreceptor Cells
Molecular Chaperones
Cones
Modulation
Antioxidant Response Elements
Oxidative stress
Chemical activation
Oxidative Stress
Pentazocine
Retinal Diseases
Proteins
Retinitis Pigmentosa
Optical Coherence Tomography
sigma-1 receptor
Optical tomography
Noise
Transcription Factors
Ligands
Genes
Gene Expression

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

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title = "The molecular chaperone sigma 1 receptor mediates rescue of retinal cone photoreceptor cells via modulation of NRF2",
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.",
keywords = "NRF2-KEAP1, NRF2-Neh luciferase assay, Oxidative stress, Retina, Retinal neuroprotection, Retinitis pigmentosa, rd10 mouse",
author = "Jing Wang and J. Zhao and X. Cui and Mysona, {Barbara A} and S. Navneet and Saul, {Alan B} and M. Ahuja and Lambert, {Nevin A} and Gazaryan, {I. G.} and Bobby Thomas and Bollinger, {Kathryn Elizabeth} and Smith, {Sylvia B}",
year = "2019",
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language = "English (US)",
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T1 - The molecular chaperone sigma 1 receptor mediates rescue of retinal cone photoreceptor cells via modulation of NRF2

AU - Wang, Jing

AU - Zhao, J.

AU - Cui, X.

AU - Mysona, Barbara A

AU - Navneet, S.

AU - Saul, Alan B

AU - Ahuja, M.

AU - Lambert, Nevin A

AU - Gazaryan, I. G.

AU - Thomas, Bobby

AU - Bollinger, Kathryn Elizabeth

AU - Smith, Sylvia B

PY - 2019/4/1

Y1 - 2019/4/1

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

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JF - Free Radical Biology and Medicine

SN - 0891-5849

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