Tandem mass tag-based proteomic analysis reveals cathepsin-mediated anti-autophagic and pro-apoptotic effects under proliferative diabetic retinopathy

Proliferative diabetic retinopathy (PDR) is a severe complication of diabetes and can cause blindness. However, the available therapeutic modalities to PDR have unsatisfactory efficacies and incur adverse effects, which is due to the paucity in the understanding of pathogenic mechanisms responsible for the disease. In this study, tandem mass tag labeling technology combined with liquid chromatography and tandem mass spectrometry were utilized to identify differentially expressed proteins in vitreous humor of patients with rhegmatogenous retinal detachment and PDR. The data are available via ProteomeXchange with identifier PXD021788. Afterwards, the downregulated protein expression of Cathepsin B, D, and L was verified in vitreous and serum of another cohort. The gene expression profiling of the 3 cathepsins was confirmed in blood cells of an extra cohort. Furthermore, in high glucose (HG)-treated retinal vascular endothelial cell cultures recapitulating the cathepsin expression patterns, Cathepsin B or D downregulation mediated the HG-induced anti-autophagic and pro-apoptotic effects, thereby may contribute to vascular lesions under hyperglycemia. This study demonstrates previously undescribed expression patterns of cathepsins, reveals a novel cathepsin-involved pathogenic mechanism under PDR, and sheds light on potential therapeutic targets to this debilitating retinal disease.