HepG2 cells-derived exosomes exacerbate blue light-induced AMD-like retinal degeneration in A2E-laden ARPE-19 cells...

Exosomes derived from hepatic cells have emerged as important mediators of inter-organ communication and may contribute to retinal degeneration associated with age-related macular degeneration (AMD) through the liver-eye axis. However, their role in AMD pathogenesis remains poorly understood. In this study, we investigated whether HepG2 cell-derived exosomes (HG-EX) exacerbate AMD-like retinal degeneration using in vitro and in vivo AMD-mimicking models. ARPE-19 cells co-treated with N-retinylidene-N-retinylethanolamine (A2E) and blue light (BL), as well as BL-exposed BALB/c mice, were pretreated with HG-EX. In AMD-mimicking ARPE-19 cells, HG-EX pretreatment significantly increased intracellular reactive oxygen species (ROS) and nitric oxide (NO) production while suppressing the expression of superoxide dismutase (SOD) and nuclear factor erythroid 2-related factor 2 (Nrf2). In addition, HG-EX altered inflammatory signaling by suppressing inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, while enhancing inflammasome-related protein expression. Apoptosis-related proteins and pro-angiogenic factors were also markedly elevated following HG-EX treatment. In AMD-mimicking mice, HG-EX administration significantly increased the retinal expression of COX-2, B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, accompanied by a reduction in the thickness of the outer segment (OS) and inner nuclear layer (INL). Collectively, these findings demonstrate that HG-EX exacerbate oxidative stress, inflammation, apoptosis, and angiogenesis in both cellular and animal models that recapitulate selected pathological features of AMD. Our results suggest that HG-EX may contribute to AMD-like retinal degeneration and warrant further investigation into their potential role in AMD pathogenesis.