αb-crystallin regulates subretinal fibrosis by modulation of epithelial-mesenchymal transition

Keijiro Ishikawa, Parameswaran G. Sreekumar, Christine Spee, Hossein Nazari, Danhong Zhu, Ram Kannan, David R. Hinton

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Subretinal fibrosis is an end stage of neovascular age-related macular degeneration, characterized by fibrous membrane formation after choroidal neovascularization. An initial step of the pathogenesis is an epithelial-mesenchymal transition (EMT) of retinal pigment epithelium cells. αB-crystallin plays multiple roles in age-related macular degeneration, including cytoprotection and angiogenesis. However, the role of αB-crystallin in subretinal EMT and fibrosis is unknown. Herein, we showed attenuation of subretinal fibrosis after regression of laser-induced choroidal neovascularization and a decrease in mesenchymal retinal pigment epithelium cells in αB-crystallin knockout mice compared with wild-type mice. αB-crystallin was prominently expressed in subretinal fibrotic lesions in mice. In vitro, overexpression of αB-crystallin induced EMT, whereas suppression of αB-crystallin induced a mesenchymal-epithelial transition. Transforming growth factor-β2-induced EMT was further enhanced by overexpression of αB-crystallin but was inhibited by suppression of αB-crystallin. Silencing of αB-crystallin inhibited multiple fibrotic processes, including cell proliferation, migration, and fibronectin production. Bone morphogenetic protein 4 up-regulated αB-crystallin, and its EMT induction was inhibited by knockdown of αB-crystallin. Furthermore, inhibition of αB-crystallin enhanced monotetraubiquitination of SMAD4, which can impair its nuclear localization. Overexpression of αB-crystallin enhanced nuclear translocation and accumulation of SMAD4 and SMAD5. Thus, αB-crystallin is an important regulator of EMT, acting as a molecular chaperone for SMAD4 and as its potential therapeutic target for preventing subretinal fibrosis development in neovascular age-related macular degeneration.

Original languageEnglish
Pages (from-to)859-873
Number of pages15
JournalAmerican Journal of Pathology
Volume186
Issue number4
DOIs
Publication statusPublished - Apr 1 2016

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Crystallins
Epithelial-Mesenchymal Transition
Fibrosis
Macular Degeneration
Choroidal Neovascularization
Retinal Pigment Epithelium
Bone Morphogenetic Protein 4
Molecular Chaperones
Cytoprotection
Transforming Growth Factors
Fibronectins
Knockout Mice
Cell Movement

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

αb-crystallin regulates subretinal fibrosis by modulation of epithelial-mesenchymal transition. / Ishikawa, Keijiro; Sreekumar, Parameswaran G.; Spee, Christine; Nazari, Hossein; Zhu, Danhong; Kannan, Ram; Hinton, David R.

In: American Journal of Pathology, Vol. 186, No. 4, 01.04.2016, p. 859-873.

Research output: Contribution to journalArticle

Ishikawa, Keijiro ; Sreekumar, Parameswaran G. ; Spee, Christine ; Nazari, Hossein ; Zhu, Danhong ; Kannan, Ram ; Hinton, David R. / αb-crystallin regulates subretinal fibrosis by modulation of epithelial-mesenchymal transition. In: American Journal of Pathology. 2016 ; Vol. 186, No. 4. pp. 859-873.
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