Insights on the involvement of (–)-epigallocatechin gallate in ER stress-mediated apoptosis in age-related macular degeneration

Abstract

Endoplasmic reticulum (ER) stress-mediated apoptosis is a well-known factor in the pathogenesis of age-related macular degeneration (AMD). ER stress leads to accumulation of misfolded proteins, which in turn activates unfolded protein response (UPR) of the cell for its survival. The prolonged UPR of ER stress promotes cell death; however, the transition between adaptation and ER stress-induced apoptosis has not been clearly understood. Hence, the present study investigates the regulatory effect of (-)-epigallocatechin gallate (EGCG) on ER stress-induced by hydrogen peroxide (HO) and disturbance of calcium homeostasis by thapsigargin (TG) in mouse retinal pigment epithelial (MRPE) cells. The oxidant molecules influenced MRPE cells showed an increased level of intracellular calcium [Ca] in ER and transferred to mitochondria through ER-mitochondrial tether site then increased ROS production. EGCG restores [Ca] homeostasis by decreasing ROS production through inhibition of prohibitin1 which regulate ER-mitochondrial tether site and inhibit apoptosis. Effect of EGCG on ER stress-mediated apoptosis was elucidated by exploring the UPR signalling pathways. EGCG downregulated GRP78, CHOP, PERK, ERO1α, IRE1α, cleaved PARP, cleaved caspase 3, caspase 12 and upregulated expression of calnexinin MRPE cells. In addition to this, inhibition of apoptosis by EGCG was also confirmed with expression of proteins Akt, PTEN and GSK3β. MRPE cells with EGCG upregulates phosphorylation of Akt at ser473 and phospho ser380 of PTEN, but phosphorylation at ser9 of GSK3β was inhibited. Further, constitutively active (myristoylated) CA-Akt transfected in MRPE cells had an increased Akt activity in EGCG influenced cells. These findings strongly suggest that antioxidant molecules inhibit cell death through the proper balancing of [Ca] and ROS production in order to maintain UPR of ER in MRPE cells. Thus, modulation of UPR signalling may provide a potential target for the therapeutic approaches of AMD.

Neurodegeneration: Keeping ATF4 on a Tight Leash

“…The UPR PERK → p- eIF2a → ATF4 pathway seems to play a significant role in photoreceptor deterioration in mice expressing aberrant proteins. Thus, we and other investigators have recently proposed that the UPR contributes markedly to retinal pathogenesis under various degenerative conditions (Gorbatyuk and Gorbatyuk, 2013 ; Zhang et al, 2014 ; Hiramatsu et al, 2015 ; Karthikeyan et al, 2017 ). Some investigators have suggested that “ER stress is a general upstream mechanism for neurodegeneration” and that “targeting ER stress molecules is a promising therapeutic strategy for neuroprotection (Huang et al, 2017 ).”…”

Chrysin Ameliorates Malfunction of Retinoid Visual Cycle through Blocking Activation of AGE-RAGE-ER Stress in Glucose-Stimulated Retinal Pigment Epithelial Cells and Diabetic Eyes

“…Moreover, ER stress is a critical adverse component of RPE cells and photoreceptors [ 53 , 54 ]. One investigation shows that the tea polyphenol (−)epigallocatechin gallate inhibited ER stress-mediated apoptotic cell death via the proper calcium homeostasis and decreased ROS production in age-related macular degeneration [ 55 ]. Bilberry extract attenuates photoinduced apoptosis and visual dysfunction via ER stress attenuation in the retina [ 54 ].…”

Epigallocatechin-3-Gallate (EGCG) Promotes Autophagy-Dependent Survival via Influencing the Balance of mTOR-AMPK Pathways upon Endoplasmic Reticulum Stress

“…Therefore, mTOR inhibitors and/or AMPK activators (such as rapamycin, resveratrol, and metyrapone) are able to postpone apoptotic cell death during excessive ER stress [ 29 , 31 ]. EGCG is able to restore Ca 2+ homeostasis suggesting its cytoprotective effect in ER stress [ 32 ]; however, the detailed mechanism of the EGCG-modulated ER stress response remains to be elucidated.…”