Activation of TGF-\u03b2 signaling induces cell death via the unfolded protein response in Fuchs endothelial corneal dystrophy

Naoki Okumura,Takahiko Sato,Theofilos Tourtas,Shigeru Kinoshita,Makiko Nakahara,Noriko Koizumi,Hirokazu Okuda,Miu Kitahara,Keisuke Hashimoto,Emi Ueda,Friedrich Kruse,Kyoko Watanabe,Ursula Schlötzer-Schrehardt

doi:10.1038/s41598-017-06924-3

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.

Highlights

Fuchs endothelial corneal dystrophy (FECD) is a slowly progressive bilateral disease of the corneal endothelium
Quantitative real-time polymerase chain reaction (PCR) assays showed that expression levels of TGF-β1 and TGF-β2 were significantly higher in Patients with FECD (n = 30) than in normal control subjects (n = 30) (2.76 and 4.36 fold, respectively) (Fig. 1a,b)
We evaluated the effect of transforming growth factor-β (TGF-β) on extracellular matrix (ECM) components and unfolded protein formation by using iFECD, which is a corneal endothelial cell model established from patients with FECD

Summary

Introduction

Fuchs endothelial corneal dystrophy (FECD) is a slowly progressive bilateral disease of the corneal endothelium. Folded proteins are packaged into ER exit vesicles, whereas improperly folded proteins are retained in the ER and are removed by proteasomal degradation, called ER-associated degradation (ERAD)[9] This highly regulated system is monitored by a conserved signaling pathway, termed the UPR10, 11. Severe ER stress, with its associated impairment of homeostasis, induces chronic activation of the UPR, resulting in apoptosis to remove rogue cells[10, 11]. The phenotypic features of FECD in the clinical setting are (1) formation of corneal guttae that are excrescences of the basement membrane (Descemet’s membrane) and (2) endothelial cell loss[18]. The mechanisms for upregulation of secretion of these ECM proteins and the association of the ECM accumulation with endothelial cell loss in FECD remain unclear.

Methods

Results

Conclusion