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Sci Rep. 2017 Jul 28;7(1):6801. doi: 10.1038/s41598-017-06924-3.

Activation of TGF-β signaling induces cell death via the unfolded protein response in Fuchs endothelial corneal dystrophy.

Author information

1
Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
2
Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
3
Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
4
Department of Ophthalmology, University of Erlangen-Nürnberg, Erlangen, Germany.
5
Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan. nkoizumi@mail.doshisha.ac.jp.

Abstract

Fuchs endothelial corneal dystrophy (FECD) is a slowly progressive bilateral disease of corneal endothelium in which accumulation of extracellular matrix (ECM) and loss of corneal endothelial cells (CECs) are phenotypic features. The corneal endothelium maintains corneal transparency by regulating water hydration; consequently, corneal endothelial dysfunction causes serious vision loss. The only therapy for corneal haziness due to corneal endothelial diseases, including FECD, is corneal transplantation using donor corneas, and no pharmaceutical treatment is available. We provide evidence that the expression levels of transforming growth factor-β (TGF-β) isoforms and TGF-β receptors are high in the corneal endothelium of patients with FECD. A cell model based on patients with FECD shows that TGF-β signaling induced a chronic overload of ECM proteins to the endoplasmic reticulum (ER), thereby enhancing the formation of unfolded protein and triggering the intrinsic apoptotic pathway through the unfolded protein response (UPR). We propose that inhibition of TGF-β signaling may represent a novel therapeutic target that suppresses cell loss as well as the accumulation of ECM in FECD.

PMID:
28754918
PMCID:
PMC5533742
DOI:
10.1038/s41598-017-06924-3
[Indexed for MEDLINE]
Free PMC Article

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