Retinal Ganglion Cell Senescence Links Diabetes to Retinal Neurodegeneration.

Background Diabetic retinopathy (DR) is a leading cause of blindness worldwide and traditionally considered a microvascular complication. However, accumulating evidence indicates that retinal neurodegeneration is also crucial in DR pathogenesis. Retinal ganglion cells (RGCs), the output neurons of the retina, are particularly vulnerable to diabetic stress. Cellular senescence has been implicated in diabetes-related tissue damage, but its contribution to RGC degeneration remains unclear. We hypothesized that diabetes contributes to retinal neurodegeneration by inducing senescence in RGCs. Methods In streptozotocin (STZ)-induced diabetic mice, retinal function was assessed via full-field electroretinography (ERG), and molecular changes were evaluated in senescence markers. The expression of p16INK4a and monocyte chemotactic protein-1 (MCP-1) in retinal tissue was evaluated by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR), and the localization of p16INK4a was confirmed by immunostaining. To explore the direct effects of senescence, primary RGCs isolated from rat retina were exposed to oxidative stress or treated with the CDK4/6 inhibitor palbociclib. The isolated RGCs were analyzed via senescence-associated β-galactosidase (SA-β-gal) staining and live-cell neurite imaging. Results The STZ-induced diabetic mice exhibited significant hyperglycemia without weight loss. ERG revealed markedly reduced amplitudes of the a-wave, b-wave, and oscillatory potentials, indicating impaired retinal neural function. Molecular analyses revealed significant upregulation of MCP-1 and p16INK4a at mRNA and protein levels. Immunostaining demonstrated p16INK4a co-expression in a subset of NeuN-positive cells within the ganglion cell layer, suggesting RGC senescence. Palbociclib-induced senescence (confirmed by SA-β-gal positivity) in vitroresulted in progressive neurite shortening in RGCs. Similarly, oxidative stress induced by antioxidant-free culture conditions caused neurite degeneration, highlighting the dual contributions of oxidative stress and senescence to RGC injury. Conclusions Cellular senescence was identified as a critical mechanism underlying RGC dysfunction in diabetes. Diabetes was found to induce retinal senescence and senescence-associated secretory phenotype activation, with RGCs exhibiting senescence-associated changes. Moreover, oxidative stress and pharmacologically induced senescence directly impaired RGC morphology and function in vitro. These results expanded our understanding of DR from a solely vascular disorder to a neurodegenerative disease, providing mechanistic insights into the role of senescence in retinal aging and neuronal susceptibility in diabetes.