X-Box binding protein 1 is essential for the anti-oxidant defense and cell survival in the retinal pigment epithelium

Yimin Zhong, Jingming Li, Joshua J. Wang, Chen Chen, Julie Thu A. Tran, Anisse Saadi, Qiang Yu, Yun zheng Le, Nawajes Mandal, Robert E. Anderson, Sarah X. Zhang

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Damage to the retinal pigment epithelium (RPE) is an early event in the pathogenesis of age-related macular degeneration (AMD). X-box binding protein 1 (XBP1) is a key transcription factor that regulates endoplasmic reticulum (ER) homeostasis and cell survival. This study aimed to delineate the role of endogenous XBP1 in the RPE. Our results show that in a rat model of light-induced retinal degeneration, XBP1 activation was suppressed in the RPE/choroid complex, accompanied by decreased anti-oxidant genes and increased oxidative stress. Knockdown of XBP1 by siRNA resulted in reduced expression of SOD1, SOD2, catalase, and glutathione synthase and sensitized RPE cells to oxidative damage. Using Cre/LoxP system, we generated a mouse line that lacks XBP1 only in RPE cells. Compared to wildtype littermates, RPE-XBP1 KO mice expressed less SOD1, SOD2, and catalase in the RPE, and had increased oxidative stress. At age 3 months and older, these mice exhibited apoptosis of RPE cells, decreased number of cone photoreceptors, shortened photoreceptor outer segment, reduced ONL thickness, and deficit in retinal function. Electron microscopy showed abnormal ultrastructure, Bruch's membrane thickening, and disrupted basal membrane infolding in XBP1-deficient RPE. These results indicate that XBP1 is an important gene involved in regulation of the anti-oxidant defense in the RPE, and that impaired activation of XBP1 may contribute to RPE dysfunction and cell death during retinal degeneration and AMD.

Original languageEnglish (US)
Article numbere38616
JournalPLoS One
Volume7
Issue number6
DOIs
StatePublished - Jun 8 2012
Externally publishedYes

Fingerprint

Retinal Pigments
Retinal Pigment Epithelium
Oxidants
cell viability
binding proteins
Cell Survival
Carrier Proteins
epithelium
antioxidant activity
pigments
Cells
Retinal Degeneration
Oxidative stress
Macular Degeneration
Catalase
catalase
mice
Oxidative Stress
X-Box Binding Protein 1
oxidative stress

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Zhong, Y., Li, J., Wang, J. J., Chen, C., Tran, J. T. A., Saadi, A., ... Zhang, S. X. (2012). X-Box binding protein 1 is essential for the anti-oxidant defense and cell survival in the retinal pigment epithelium. PLoS One, 7(6), [e38616]. https://doi.org/10.1371/journal.pone.0038616

X-Box binding protein 1 is essential for the anti-oxidant defense and cell survival in the retinal pigment epithelium. / Zhong, Yimin; Li, Jingming; Wang, Joshua J.; Chen, Chen; Tran, Julie Thu A.; Saadi, Anisse; Yu, Qiang; Le, Yun zheng; Mandal, Nawajes; Anderson, Robert E.; Zhang, Sarah X.

In: PLoS One, Vol. 7, No. 6, e38616, 08.06.2012.

Research output: Contribution to journalArticle

Zhong, Y, Li, J, Wang, JJ, Chen, C, Tran, JTA, Saadi, A, Yu, Q, Le, YZ, Mandal, N, Anderson, RE & Zhang, SX 2012, 'X-Box binding protein 1 is essential for the anti-oxidant defense and cell survival in the retinal pigment epithelium', PLoS One, vol. 7, no. 6, e38616. https://doi.org/10.1371/journal.pone.0038616
Zhong, Yimin ; Li, Jingming ; Wang, Joshua J. ; Chen, Chen ; Tran, Julie Thu A. ; Saadi, Anisse ; Yu, Qiang ; Le, Yun zheng ; Mandal, Nawajes ; Anderson, Robert E. ; Zhang, Sarah X. / X-Box binding protein 1 is essential for the anti-oxidant defense and cell survival in the retinal pigment epithelium. In: PLoS One. 2012 ; Vol. 7, No. 6.
@article{c265cbb2df7c4983a53739d5c44a4916,
title = "X-Box binding protein 1 is essential for the anti-oxidant defense and cell survival in the retinal pigment epithelium",
abstract = "Damage to the retinal pigment epithelium (RPE) is an early event in the pathogenesis of age-related macular degeneration (AMD). X-box binding protein 1 (XBP1) is a key transcription factor that regulates endoplasmic reticulum (ER) homeostasis and cell survival. This study aimed to delineate the role of endogenous XBP1 in the RPE. Our results show that in a rat model of light-induced retinal degeneration, XBP1 activation was suppressed in the RPE/choroid complex, accompanied by decreased anti-oxidant genes and increased oxidative stress. Knockdown of XBP1 by siRNA resulted in reduced expression of SOD1, SOD2, catalase, and glutathione synthase and sensitized RPE cells to oxidative damage. Using Cre/LoxP system, we generated a mouse line that lacks XBP1 only in RPE cells. Compared to wildtype littermates, RPE-XBP1 KO mice expressed less SOD1, SOD2, and catalase in the RPE, and had increased oxidative stress. At age 3 months and older, these mice exhibited apoptosis of RPE cells, decreased number of cone photoreceptors, shortened photoreceptor outer segment, reduced ONL thickness, and deficit in retinal function. Electron microscopy showed abnormal ultrastructure, Bruch's membrane thickening, and disrupted basal membrane infolding in XBP1-deficient RPE. These results indicate that XBP1 is an important gene involved in regulation of the anti-oxidant defense in the RPE, and that impaired activation of XBP1 may contribute to RPE dysfunction and cell death during retinal degeneration and AMD.",
author = "Yimin Zhong and Jingming Li and Wang, {Joshua J.} and Chen Chen and Tran, {Julie Thu A.} and Anisse Saadi and Qiang Yu and Le, {Yun zheng} and Nawajes Mandal and Anderson, {Robert E.} and Zhang, {Sarah X.}",
year = "2012",
month = "6",
day = "8",
doi = "10.1371/journal.pone.0038616",
language = "English (US)",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "6",

}

TY - JOUR

T1 - X-Box binding protein 1 is essential for the anti-oxidant defense and cell survival in the retinal pigment epithelium

AU - Zhong, Yimin

AU - Li, Jingming

AU - Wang, Joshua J.

AU - Chen, Chen

AU - Tran, Julie Thu A.

AU - Saadi, Anisse

AU - Yu, Qiang

AU - Le, Yun zheng

AU - Mandal, Nawajes

AU - Anderson, Robert E.

AU - Zhang, Sarah X.

PY - 2012/6/8

Y1 - 2012/6/8

N2 - Damage to the retinal pigment epithelium (RPE) is an early event in the pathogenesis of age-related macular degeneration (AMD). X-box binding protein 1 (XBP1) is a key transcription factor that regulates endoplasmic reticulum (ER) homeostasis and cell survival. This study aimed to delineate the role of endogenous XBP1 in the RPE. Our results show that in a rat model of light-induced retinal degeneration, XBP1 activation was suppressed in the RPE/choroid complex, accompanied by decreased anti-oxidant genes and increased oxidative stress. Knockdown of XBP1 by siRNA resulted in reduced expression of SOD1, SOD2, catalase, and glutathione synthase and sensitized RPE cells to oxidative damage. Using Cre/LoxP system, we generated a mouse line that lacks XBP1 only in RPE cells. Compared to wildtype littermates, RPE-XBP1 KO mice expressed less SOD1, SOD2, and catalase in the RPE, and had increased oxidative stress. At age 3 months and older, these mice exhibited apoptosis of RPE cells, decreased number of cone photoreceptors, shortened photoreceptor outer segment, reduced ONL thickness, and deficit in retinal function. Electron microscopy showed abnormal ultrastructure, Bruch's membrane thickening, and disrupted basal membrane infolding in XBP1-deficient RPE. These results indicate that XBP1 is an important gene involved in regulation of the anti-oxidant defense in the RPE, and that impaired activation of XBP1 may contribute to RPE dysfunction and cell death during retinal degeneration and AMD.

AB - Damage to the retinal pigment epithelium (RPE) is an early event in the pathogenesis of age-related macular degeneration (AMD). X-box binding protein 1 (XBP1) is a key transcription factor that regulates endoplasmic reticulum (ER) homeostasis and cell survival. This study aimed to delineate the role of endogenous XBP1 in the RPE. Our results show that in a rat model of light-induced retinal degeneration, XBP1 activation was suppressed in the RPE/choroid complex, accompanied by decreased anti-oxidant genes and increased oxidative stress. Knockdown of XBP1 by siRNA resulted in reduced expression of SOD1, SOD2, catalase, and glutathione synthase and sensitized RPE cells to oxidative damage. Using Cre/LoxP system, we generated a mouse line that lacks XBP1 only in RPE cells. Compared to wildtype littermates, RPE-XBP1 KO mice expressed less SOD1, SOD2, and catalase in the RPE, and had increased oxidative stress. At age 3 months and older, these mice exhibited apoptosis of RPE cells, decreased number of cone photoreceptors, shortened photoreceptor outer segment, reduced ONL thickness, and deficit in retinal function. Electron microscopy showed abnormal ultrastructure, Bruch's membrane thickening, and disrupted basal membrane infolding in XBP1-deficient RPE. These results indicate that XBP1 is an important gene involved in regulation of the anti-oxidant defense in the RPE, and that impaired activation of XBP1 may contribute to RPE dysfunction and cell death during retinal degeneration and AMD.

UR - http://www.scopus.com/inward/record.url?scp=84862012177&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862012177&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0038616

DO - 10.1371/journal.pone.0038616

M3 - Article

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 6

M1 - e38616

ER -