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

Okumura, Naoki; Hashimoto, Keisuke; Kitahara, Miu; Okuda, Hiroyuki; Ueda, Emi; Watanabe, Kyoko; Nakahara, Makiko; Sato, Takahiko; Kinoshita, Shigeru; Tourtas, Theofilos; Schlötzer‐Schrehardt, Ursula; Kruse, Friedrich E.; Koizumi, Noriko

doi:10.1038/s41598-017-06924-3

Cited by 59 publications

(49 citation statements)

References 39 publications

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“…As in the differentiation of other professional secretory cells such as plasma cells [39], the increased flux of newly translated proteins represents a challenge to ER proteostasis and can lead to activation of ER stress response pathways, including ATF6 [40]. ATF6, along with other ER stress pathways, was reported to be activated with TGFβ treatment [41]. Furthermore, amelioration of ER stress, through treatment with chemical chaperones 4-PBA or TUDCA, has been shown to reduce fibrosis and TGFβ signaling [42,43].…”

Section: Discussionmentioning

confidence: 99%

The ER Unfolded Protein Response Effector, ATF6, Reduces Cardiac Fibrosis and Decreases Activation of Cardiac Fibroblasts

Stauffer

Blackwood

Azizi

et al. 2020

IJMS

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Activating transcription factor-6 α (ATF6) is one of the three main sensors and effectors of the endoplasmic reticulum (ER) stress response and, as such, it is critical for protecting the heart and other tissues from a variety of environmental insults and disease states. In the heart, ATF6 has been shown to protect cardiac myocytes. However, its roles in other cell types in the heart are unknown. Here we show that ATF6 decreases the activation of cardiac fibroblasts in response to the cytokine, transforming growth factor β (TGFβ), which can induce fibroblast trans-differentiation into a myofibroblast phenotype through signaling via the TGFβ–Smad pathway. ATF6 activation suppressed fibroblast contraction and the induction of α smooth muscle actin (αSMA). Conversely, fibroblasts were hyperactivated when ATF6 was silenced or deleted. ATF6 thus represents a novel inhibitor of the TGFβ–Smad axis of cardiac fibroblast activation.

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Section: Discussionmentioning

confidence: 99%

The ER Unfolded Protein Response Effector, ATF6, Reduces Cardiac Fibrosis and Decreases Activation of Cardiac Fibroblasts

Stauffer

Blackwood

Azizi

et al. 2020

IJMS

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“…In addition, treatment options for preserving the release of functional ER calcium suppress cytokine-mediated beta cell death in diabetes 36 . Recently, ER stress was discovered to trigger the apoptosis of corneal endothelial cells through the intrinsic signaling pathway 37 , 38 . Thus, we postulated that the chronic elevation of aqueous cytokine levels may initiate the apoptosis of corneal endothelial cells via oxidative or ER stress.…”

Section: Discussionmentioning

confidence: 99%

Association between corneal endothelial cell densities and elevated cytokine levels in the aqueous humor

Yagi-Yaguchi

Yamaguchi

Higa

et al. 2017

Sci Rep

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Annual reduction rate of corneal endothelial cell density (ECD) varies among etiologies, however, the cause of chronic endothelial cell loss is still unknown. We recently reported the elevation of inflammatory cytokines in the aqueous humor (AqH) in eyes with bullous keratopathy and low ECD. To evaluate the association between ECD and aqueous cytokine levels, we collected a total of 157 AqH samples prospectively. The AqH levels of cytokines were measured and multivariate analyses were conducted to find the correlation between ECD, aqueous cytokine levels and clinical factors, such as number of previous intraocular surgeries and protein concentration in AqH. As a result, ECD was negatively correlated with specific cytokine levels, including IL-1α, IL-4, IL-13, MIP-1β, TNF-α and E-selectin (all P < 0.05). The aqueous cytokine levels showed different correlations with these clinical factors; the number of previous intraocular surgeries was associated with all cytokines except MIP-1α. The AqH protein concentration and the status of intraocular lens showed similar patterns of elevation of IL-1α, IL-4, IL-6, IL-8, IL-10, IL-13, IL-17A, MIP-1β, MCP-1, E-selectin, P-selectin and sICAM-1. In conclusion, elevation of AqH cytokine levels was associated with reduced ECDs. AqH cytokine levels showed significant correlations with clinical factors associated with low ECDs.

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“…Recently, our group showed that ECM components, such as type I collagen and fibronectin, form aggregates of unfolded proteins in the corneal endothelium of FECD patients [ 41 ]. We also showed that activation of transforming growth factor-β (TGF-β) signaling causes a chronic overload of ECM proteins within the ER, which induces an accumulation of unfolded protein and activation of the intrinsic apoptotic pathway through the UPR [ 42 ]. The genetic background underlying the UPR induction is not yet elucidated; however, accumulating evidence supports a role for the UPR and associated apoptosis in FECD.…”

Section: Pathophisiologymentioning

confidence: 99%

Perspective of Future Potent Therapies for Fuchs Endothelial Corneal Dystrophy

Okumura¹,

Koizumi²

2018

TOOPHTJ

Self Cite

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Background:Fuchs Endothelial Corneal Dystrophy (FECD) is a progressive disease that affects the corneal endothelium in both eyes. Recent studies have identified a novel genetic basis for FECD, and basic research findings have provided evidence for its underlying pathophysiology. Since its first description by Ernst Fuchs in 1910, the only therapeutic choice has been corneal transplantation using donor corneas. However, accumulating evidence suggests that a change in this “rule” may be imminent.Conclusions:This article reviews the current knowledge of the genetics and pathophysiology of FECD, and it introduces some potent therapeutic modalities that show promise as new treatments for this disorder.

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

Cited by 59 publications

References 39 publications

The ER Unfolded Protein Response Effector, ATF6, Reduces Cardiac Fibrosis and Decreases Activation of Cardiac Fibroblasts

The ER Unfolded Protein Response Effector, ATF6, Reduces Cardiac Fibrosis and Decreases Activation of Cardiac Fibroblasts

Association between corneal endothelial cell densities and elevated cytokine levels in the aqueous humor

Perspective of Future Potent Therapies for Fuchs Endothelial Corneal Dystrophy

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