Reduced Glutathione Level Promotes Epithelial-Mesenchymal Transition in Lens Epithelial Cells via a Wnt/β-Catenin–Mediated Pathway

Relevance for Cataract Therapy

Zongbo Wei, Jane Caty, Jeremy Whitson, Amy D. Zhang, Ramkumar Srinivasagan, Terrance J. Kavanagh, Hong Yan, Xingjun Fan

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The epithelial-mesenchymal transition (EMT) process plays a pivotal role in the pathogenesis of posterior capsular opacification because of remnant lens epithelial cell proliferation, migration, and transformation after cataract surgery. The latter, we hypothesize, may result in posterior capsule wrinkling and opacification because of a profound change in the lens growth environment via a 1000-fold reduction of extracellular glutathione (GSH) levels. To test this hypothesis, we investigated the EMT process in cell culture and GSH biosynthesis deficiency mouse models. Our data indicate a dramatic increase of pro-EMT markers, such as type I collagen, α-smooth muscle actin, vimentin, and fibronectin, under conditions of lens GSH depletion. Further study suggests that decreased GSH triggers the Wnt/β-catenin signal transduction pathway, independent of transforming growth factor-β. Equally important, the antioxidants N-acetyl cysteine and GSH ethyl ester could significantly attenuate the EMT signaling stimulated by decreased GSH levels. These findings were further confirmed by mock cataract surgery in both gamma glutamyl-cysteine ligase, catalytic subunit, and gamma glutamyl-cysteine ligase, modifier subunit, knockout mouse models. Remarkably, increased EMT marker expression, β-catenin activation, and translocation into the nucleus were found in both knockout mice compared with the wild type, and such increased expression could be significantly attenuated by N-acetyl cysteine or GSH ethyl ester treatment. This study, for the first time we believe, links oxidative stress to lens fibrosis and posterior capsular opacification formation via EMT-mediated mechanisms.

Original languageEnglish (US)
Pages (from-to)2399-2412
Number of pages14
JournalAmerican Journal of Pathology
Volume187
Issue number11
DOIs
StatePublished - Nov 1 2017
Externally publishedYes

Fingerprint

Wnt Signaling Pathway
Epithelial-Mesenchymal Transition
Cataract
Lenses
Glutathione
Epithelial Cells
Cysteine
Catenins
Ligases
Knockout Mice
Therapeutics
Capsule Opacification
Transforming Growth Factors
Vimentin
Collagen Type I
Fibronectins
Cell Movement
Smooth Muscle
Actins
Signal Transduction

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Reduced Glutathione Level Promotes Epithelial-Mesenchymal Transition in Lens Epithelial Cells via a Wnt/β-Catenin–Mediated Pathway : Relevance for Cataract Therapy. / Wei, Zongbo; Caty, Jane; Whitson, Jeremy; Zhang, Amy D.; Srinivasagan, Ramkumar; Kavanagh, Terrance J.; Yan, Hong; Fan, Xingjun.

In: American Journal of Pathology, Vol. 187, No. 11, 01.11.2017, p. 2399-2412.

Research output: Contribution to journalArticle

Wei, Zongbo ; Caty, Jane ; Whitson, Jeremy ; Zhang, Amy D. ; Srinivasagan, Ramkumar ; Kavanagh, Terrance J. ; Yan, Hong ; Fan, Xingjun. / Reduced Glutathione Level Promotes Epithelial-Mesenchymal Transition in Lens Epithelial Cells via a Wnt/β-Catenin–Mediated Pathway : Relevance for Cataract Therapy. In: American Journal of Pathology. 2017 ; Vol. 187, No. 11. pp. 2399-2412.
@article{89f66c71d97f4561b42b6a5332383b11,
title = "Reduced Glutathione Level Promotes Epithelial-Mesenchymal Transition in Lens Epithelial Cells via a Wnt/β-Catenin–Mediated Pathway: Relevance for Cataract Therapy",
abstract = "The epithelial-mesenchymal transition (EMT) process plays a pivotal role in the pathogenesis of posterior capsular opacification because of remnant lens epithelial cell proliferation, migration, and transformation after cataract surgery. The latter, we hypothesize, may result in posterior capsule wrinkling and opacification because of a profound change in the lens growth environment via a 1000-fold reduction of extracellular glutathione (GSH) levels. To test this hypothesis, we investigated the EMT process in cell culture and GSH biosynthesis deficiency mouse models. Our data indicate a dramatic increase of pro-EMT markers, such as type I collagen, α-smooth muscle actin, vimentin, and fibronectin, under conditions of lens GSH depletion. Further study suggests that decreased GSH triggers the Wnt/β-catenin signal transduction pathway, independent of transforming growth factor-β. Equally important, the antioxidants N-acetyl cysteine and GSH ethyl ester could significantly attenuate the EMT signaling stimulated by decreased GSH levels. These findings were further confirmed by mock cataract surgery in both gamma glutamyl-cysteine ligase, catalytic subunit, and gamma glutamyl-cysteine ligase, modifier subunit, knockout mouse models. Remarkably, increased EMT marker expression, β-catenin activation, and translocation into the nucleus were found in both knockout mice compared with the wild type, and such increased expression could be significantly attenuated by N-acetyl cysteine or GSH ethyl ester treatment. This study, for the first time we believe, links oxidative stress to lens fibrosis and posterior capsular opacification formation via EMT-mediated mechanisms.",
author = "Zongbo Wei and Jane Caty and Jeremy Whitson and Zhang, {Amy D.} and Ramkumar Srinivasagan and Kavanagh, {Terrance J.} and Hong Yan and Xingjun Fan",
year = "2017",
month = "11",
day = "1",
doi = "10.1016/j.ajpath.2017.07.018",
language = "English (US)",
volume = "187",
pages = "2399--2412",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "11",

}

TY - JOUR

T1 - Reduced Glutathione Level Promotes Epithelial-Mesenchymal Transition in Lens Epithelial Cells via a Wnt/β-Catenin–Mediated Pathway

T2 - Relevance for Cataract Therapy

AU - Wei, Zongbo

AU - Caty, Jane

AU - Whitson, Jeremy

AU - Zhang, Amy D.

AU - Srinivasagan, Ramkumar

AU - Kavanagh, Terrance J.

AU - Yan, Hong

AU - Fan, Xingjun

PY - 2017/11/1

Y1 - 2017/11/1

N2 - The epithelial-mesenchymal transition (EMT) process plays a pivotal role in the pathogenesis of posterior capsular opacification because of remnant lens epithelial cell proliferation, migration, and transformation after cataract surgery. The latter, we hypothesize, may result in posterior capsule wrinkling and opacification because of a profound change in the lens growth environment via a 1000-fold reduction of extracellular glutathione (GSH) levels. To test this hypothesis, we investigated the EMT process in cell culture and GSH biosynthesis deficiency mouse models. Our data indicate a dramatic increase of pro-EMT markers, such as type I collagen, α-smooth muscle actin, vimentin, and fibronectin, under conditions of lens GSH depletion. Further study suggests that decreased GSH triggers the Wnt/β-catenin signal transduction pathway, independent of transforming growth factor-β. Equally important, the antioxidants N-acetyl cysteine and GSH ethyl ester could significantly attenuate the EMT signaling stimulated by decreased GSH levels. These findings were further confirmed by mock cataract surgery in both gamma glutamyl-cysteine ligase, catalytic subunit, and gamma glutamyl-cysteine ligase, modifier subunit, knockout mouse models. Remarkably, increased EMT marker expression, β-catenin activation, and translocation into the nucleus were found in both knockout mice compared with the wild type, and such increased expression could be significantly attenuated by N-acetyl cysteine or GSH ethyl ester treatment. This study, for the first time we believe, links oxidative stress to lens fibrosis and posterior capsular opacification formation via EMT-mediated mechanisms.

AB - The epithelial-mesenchymal transition (EMT) process plays a pivotal role in the pathogenesis of posterior capsular opacification because of remnant lens epithelial cell proliferation, migration, and transformation after cataract surgery. The latter, we hypothesize, may result in posterior capsule wrinkling and opacification because of a profound change in the lens growth environment via a 1000-fold reduction of extracellular glutathione (GSH) levels. To test this hypothesis, we investigated the EMT process in cell culture and GSH biosynthesis deficiency mouse models. Our data indicate a dramatic increase of pro-EMT markers, such as type I collagen, α-smooth muscle actin, vimentin, and fibronectin, under conditions of lens GSH depletion. Further study suggests that decreased GSH triggers the Wnt/β-catenin signal transduction pathway, independent of transforming growth factor-β. Equally important, the antioxidants N-acetyl cysteine and GSH ethyl ester could significantly attenuate the EMT signaling stimulated by decreased GSH levels. These findings were further confirmed by mock cataract surgery in both gamma glutamyl-cysteine ligase, catalytic subunit, and gamma glutamyl-cysteine ligase, modifier subunit, knockout mouse models. Remarkably, increased EMT marker expression, β-catenin activation, and translocation into the nucleus were found in both knockout mice compared with the wild type, and such increased expression could be significantly attenuated by N-acetyl cysteine or GSH ethyl ester treatment. This study, for the first time we believe, links oxidative stress to lens fibrosis and posterior capsular opacification formation via EMT-mediated mechanisms.

UR - http://www.scopus.com/inward/record.url?scp=85030475484&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85030475484&partnerID=8YFLogxK

U2 - 10.1016/j.ajpath.2017.07.018

DO - 10.1016/j.ajpath.2017.07.018

M3 - Article

VL - 187

SP - 2399

EP - 2412

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 11

ER -