Abstract
Purpose :
Although the pathophysiology of Fuchs endothelial corneal dystrophy (FECD) has not yet to be clarified, the activation of transforming growth factor-β (TGF-β) signaling may lead to apoptosis via endoplasmic reticulum (ER) stress due to the accumulation of unfolded proteins. Our research team at Kyoto University developed a novel ER stress inhibitor that can refold and degrade an unfolded protein. This study tested the feasibility of using this ER stress inhibitor as a potential therapeutic drug for FECD.
Methods :
Corneal endothelial cells (CECs) established from patients with FECD were cultured (iFECD), and ER stress and cell death were induced by treating the cells with TGF-β2 (10 ng/ml). The iFECD cells were then treated with ER stress inhibitor (1 and 10 μM), and the formation of unfolded proteins was investigated by aggresome staining. The expression of apoptotic and ER stress proteins was investigated by western blotting. The effect of ER stress inhibitor on mitochondrial membrane potential was investigated by staining with JC-1.
Results :
Phase contrast images showed that TGF-β2 induced cell death, but the ER stress inhibitor suppressed TGF-β2–mediated cell death. TGF-β2 induced the staining of aggresomes, indicating the formation of unfolded proteins, while it was suppressed by the ER stress inhibitor. The expression of apoptotic proteins (Caspase3, PARP) and ER stress markers (PERK, IRE1, ATF6, and CHOP) were upregulated by TGF-β2, while the ER stress inhibitor suppressed the expression of these proteins. The mitochondrial membrane potential was decreased by TGF-β2 treatment, whereas ER stress inhibitors maintained it.
Conclusions :
ER stress inhibition suppresses apoptosis of FECD model cells by suppressing the unfolded protein response. The ER stress inhibitor used here might be a new modality for the treatment of FECD.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.