Abstract
Accumulation of lipofuscin in the retinal pigment epithelium (RPE) is considered a major cause of RPE dysfunction and senescence in age-related macular degeneration (AMD), and N-retinylidene-N-retinylethanolamine (A2E) is the main fluorophore identified in lipofuscin from aged human eyes. Here, human-induced pluripotent stem cell (iPSC)-RPE was generated from healthy individuals to reveal proteomic changes associated with A2E-related RPE cell senescence. A novel RPE cell senescence-related protein, high-mobility group box 1 (HMGB1), was identified based on proteomic mass spectrometry measurements on iPSC-RPE with A2E treatment. Furthermore, HMGB1 upregulated Caveolin-1, which also was related RPE cell senescence. To investigate whether changes in HMGB1 and Caveolin-1 expression under A2E exposure contribute to RPE cell senescence, human ARPE-19 cells were stimulated with A2E; expression of HMGB1, Caveolin-1, tight junction proteins and senescent phenotypes were verified. HMGB1 inhibition alleviated A2E induced cell senescence. Migration of RPE cells was evaluated. Notably, A2E less than or equal to 10μM induced both HMGB1 and Caveolin-1 protein upregulation and HMGB1 translocation, while Caveolin-1 expression was downregulated when there was more than 10μM A2E. Our data indicate that A2E-induced upregulation of HMGB1、Caveolin-1 and HMGB1 release may relate to RPE cell senescence and play a role in the pathogenesis of AMD.
Highlights
Age-related macular degeneration (AMD) is the leading cause of vision loss in older adults worldwide [1]
Representative proteomic MS-based analyses of proteins from A2Etreated cells versus untreated cells are depicted in a volcano plot in Figure 1B, where the -log10(P value) was plotted against the log2(fold change A2E Treatment/Control)
We arranged the ratio of A2E treatment/ control expression from large to small and found that the high-mobility group box 1(HMGB1), which is marked with a red arrowhead, was upregulated 76-fold in the A2E treatment group compared to the control (p value=0.00578, Table 1)
Summary
Age-related macular degeneration (AMD) is the leading cause of vision loss in older adults worldwide [1]. AMD can be classified into early-stage or late-stage AMD The latter is characterized by neovascularization (wet AMD), geographic atrophy (dry AMD), or both [2]. Early-stage AMD is characterized a limited amount of drusen, which is mainly caused by lipid and protein accumulation and thought to contribute to astrophic changes. Neovascular changes or geographic atrophy involving the macular area can be present in patients for years. Dry AMD manifests as well-demarcated areas, providing direct visualization of the underlying choroidal vessels due to atrophy of photoreceptor and retinal pigment epithelium (RPE) cells; wet AMD is characterized by the development of choroidal neo-vascularization (CNV) [3]. The young status of iPSC-RPE may provide an excellent means for observing changes in protein expression during the process of RPE cell aging [7]
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