ИСТИНА

Oxidative stress is considered a shared factor inducing retinal damage in age­related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma, prevalent blind­causing diseases that affect different retinal neurons. Oxidative conditions are associated with the release of mobile zinc due to the oxidation of zinc buffer proteins (metallothioneins). In this study, we examine whether excess zinc is a common mediator of neurodegeneration in various retinal diseases and what are the mechanisms underlying its effects. Animal studies demonstrated elevated levels of mobile zinc associated with ocular hypertension, photodamage and inflammation, key drivers of glaucoma, AMD, and DR. Zinc was shown to exert a rapid and pronounced cytotoxic effect in retinal cell models. Molecular fishing in retinal extracts followed by mass spectrometric identification revealed candidate proteins that may mediate pro­apoptotic zinc signaling, among which were components of the retinoic acid (RA) cascade that regulates gene expression in the retina. Western blotting and targeted lipidomics analysis demonstrated activation of RA signaling in response to zinc stress. Knockdown of RA cascade genes affected the susceptibility of retinal model cells to zinc­induced cytotoxicity. Transcriptome analysis of cells subjected to zinc stress revealed upregulation of zinc transporters and chaperones, followed by downregulation of neurotrophic factors and triggering of apoptotic pathways. These processes were associated with activation of RA­dependent genes, including transcription factors that play a critical role in the regulation of neuronal proliferation and apoptosis in the retina. Based on these results, it is suggested that retinal cells are sensitive to zinc stress and the action of zinc is mediated by the RA cascade, which may be a promising target for the treatment of retinal degenerative diseases. This work was supported by the Russian Science Foundation Grant No. 24­15­00171.