초록 열기/닫기 버튼
The disruption of the retinal pigment epithelium (RPE), for example, through oxidative damage, is a common factorunderlying age-related macular degeneration (AMD). Aberrant autophagy also contributes to AMD pathology, asautophagy maintains RPE homeostasis to ensure blood–retinal barrier (BRB) integrity and protect photoreceptors. Thioredoxin-interacting protein (TXNIP) promotes cellular oxidative stress by inhibiting thioredoxin reducing capacityand is in turn inversely regulated by reactive oxygen species levels; however, its role in oxidative stress-induced RPEcell dysfunction and the mechanistic link between TXNIP and autophagy are largely unknown. Here, we observed thatTXNIP expression was rapidly downregulated in RPE cells under oxidative stress and that RPE cell proliferation wasdecreased. TXNIP knockdown demonstrated that the suppression of proliferation resulted from TXNIP depletioninducedautophagic flux, causing increased p53 activation via nuclear localization, which in turn enhanced AMPKphosphorylation and activation. Moreover, TXNIP downregulation further negatively impacted BRB integrity bydisrupting RPE cell tight junctions and enhancing cell motility by phosphorylating, and thereby activating, Src kinase. Finally, we also revealed that TXNIP knockdown upregulated HIF-1α, leading to the enhanced secretion of VEGF fromRPE cells and the stimulation of angiogenesis in cocultured human retinal microvascular endothelial cells. Thissuggests that the exposure of RPE cells to sustained oxidative stress may promote choroidal neovascularization,another AMD pathology. Together, these findings reveal three distinct mechanisms by which TXNIP downregulationdisrupts RPE cell function and thereby exacerbates AMD pathogenesis. Accordingly, reinforcing or restoring BRBintegrity by targeting TXNIP may serve as an effective therapeutic strategy for preventing or attenuatingphotoreceptor damage in AMD.
