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

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 reg...

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Autores principales:	Naoki Okumura, Keisuke Hashimoto, Miu Kitahara, Hirokazu Okuda, Emi Ueda, Kyoko Watanabe, Makiko Nakahara, Takahiko Sato, Shigeru Kinoshita, Theofilos Tourtas, Ursula Schlötzer-Schrehardt, Friedrich Kruse, Noriko Koizumi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2bcf614c5cd14afdb25ec7f9a4fe5f01
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spelling	oai:doaj.org-article:2bcf614c5cd14afdb25ec7f9a4fe5f012021-12-02T12:32:19ZActivation of TGF-β signaling induces cell death via the unfolded protein response in Fuchs endothelial corneal dystrophy10.1038/s41598-017-06924-32045-2322https://doaj.org/article/2bcf614c5cd14afdb25ec7f9a4fe5f012017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06924-3https://doaj.org/toc/2045-2322Abstract 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.Naoki OkumuraKeisuke HashimotoMiu KitaharaHirokazu OkudaEmi UedaKyoko WatanabeMakiko NakaharaTakahiko SatoShigeru KinoshitaTheofilos TourtasUrsula Schlötzer-SchrehardtFriedrich KruseNoriko KoizumiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Naoki Okumura Keisuke Hashimoto Miu Kitahara Hirokazu Okuda Emi Ueda Kyoko Watanabe Makiko Nakahara Takahiko Sato Shigeru Kinoshita Theofilos Tourtas Ursula Schlötzer-Schrehardt Friedrich Kruse Noriko Koizumi Activation of TGF-β signaling induces cell death via the unfolded protein response in Fuchs endothelial corneal dystrophy
description	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.
format	article
author	Naoki Okumura Keisuke Hashimoto Miu Kitahara Hirokazu Okuda Emi Ueda Kyoko Watanabe Makiko Nakahara Takahiko Sato Shigeru Kinoshita Theofilos Tourtas Ursula Schlötzer-Schrehardt Friedrich Kruse Noriko Koizumi
author_facet	Naoki Okumura Keisuke Hashimoto Miu Kitahara Hirokazu Okuda Emi Ueda Kyoko Watanabe Makiko Nakahara Takahiko Sato Shigeru Kinoshita Theofilos Tourtas Ursula Schlötzer-Schrehardt Friedrich Kruse Noriko Koizumi
author_sort	Naoki Okumura
title	Activation of TGF-β signaling induces cell death via the unfolded protein response in Fuchs endothelial corneal dystrophy
title_short	Activation of TGF-β signaling induces cell death via the unfolded protein response in Fuchs endothelial corneal dystrophy
title_full	Activation of TGF-β signaling induces cell death via the unfolded protein response in Fuchs endothelial corneal dystrophy
title_fullStr	Activation of TGF-β signaling induces cell death via the unfolded protein response in Fuchs endothelial corneal dystrophy
title_full_unstemmed	Activation of TGF-β signaling induces cell death via the unfolded protein response in Fuchs endothelial corneal dystrophy
title_sort	activation of tgf-β signaling induces cell death via the unfolded protein response in fuchs endothelial corneal dystrophy
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/2bcf614c5cd14afdb25ec7f9a4fe5f01
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Activation of TGF-β signaling induces cell death via the unfolded protein response in Fuchs endothelial corneal dystrophy

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