Spermidine Attenuates Oxidative Stress-Induced Apoptosis via Blocking Ca2+ Overload in Retinal Pigment Epithelial Cells Independently of ROS

Abstract

Retinal pigment epithelial (RPE) cells occupy the outer layer of the retina and perform various biological functions. Oxidative damage to RPE cells is a major risk factor for retinal degeneration that ultimately leads to vision loss. In this study, we investigated the role of spermidine in a hydrogen peroxide (H2O2)-induced oxidative stress model using human RPE cells. Our findings showed that 300 μM H2O2 increased cytotoxicity, apoptosis, and cell cycle arrest in the G2/M phase, whereas these effects were markedly suppressed by 10 μM spermidine. Furthermore, spermidine significantly reduced H2O2-induced mitochondrial dysfunction including mitochondrial membrane potential and mitochondrial activity. Although spermidine displays antioxidant properties, the generation of intracellular reactive oxygen species (ROS) upon H2O2 insult was not regulated by spermidine. Spermidine did suppress the increase in cytosolic Ca2+ levels resulting from endoplasmic reticulum stress in H2O2-stimulated human RPE cells. Treatment with a cytosolic Ca2+ chelator markedly reversed H2O2-induced cellular dysfunction. Overall, spermidine protected against H2O2-induced cellular damage by blocking the increase of intracellular Ca2+ independently of ROS. These results suggest that spermidine protects RPE cells from oxidative stress, which could be a useful treatment for retinal diseases.

LXA4 protects against blue-light induced retinal degeneration in human A2E-laden RPE cells and Balb-c mice

“…Oxidative stress has been proven to initiate the development of AMD (41). It has been reported that it increases ROS generation, which leads to RPE cell apoptosis (42). Additionally, NRF2/HO1 signaling is a defense mechanism against the oxidative stress of RPE cells (43).…”

Research Progress and Potential Applications of Spermidine in Ocular Diseases

“…Spermidine has a wide range of biofunctions: anti-aging, autophagy induction, cell proliferation activation, anti-inflammation, anti-oxidation, and ion channel regulation [ 14 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ].…”

“…In the immune system, it helps to maintain mucosal homeostasis of the intestine, which is under excessive inflammation [ 10 , 11 , 12 ]. It also facilitates the regeneration and migration of epithelial cells, thus protecting barrier function in some cases, such as retinal pigment epithelial cells (RPEs) and colon epithelial cells [ 10 , 13 , 14 , 15 ].…”

“…In the light of such protective effects, researchers have recently expanded its application to ocular diseases such as dry eye syndrome, bacterial keratitis, cataracts, glaucoma, optic nerve injury, and age-related macular degeneration (AMD) [ 14 , 16 , 17 , 18 , 19 , 20 ]. These diseases pose a significant threat to human vision worldwide, especially among working-aged groups, thus exerting a heavy burden on families and society [ 21 , 22 ].…”

The Protective Effect of Topical Spermidine on Dry Eye Disease with Retinal Damage Induced by Diesel Particulate Matter2.5

“…Moreover, Guo et al [ 25 ] suggested that spermidine alleviates H 2 O 2 -mediated retinal ganglion cell death and prevents optic nerve demyelination in autoimmune encephalomyelitis mice. Previously, we demonstrated that spermidine suppressed H 2 O 2 -induced apoptosis in retinal pigment epithelial cells by blocking calcium overload [ 26 ]. Even though spermidine has a protective effect on the retina and optic nerve, the effect of topical administration of spermidine on the ocular system has not been sufficiently elucidated.…”