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Prolonged use of dexamethasone (DEX) increases intraocular pressure (IOP) and the risk of glaucoma. Recent studies have shown that DEX upregulates thrombospondin-1 ( THBS1 ) gene expression and induces dysregulation of macroautophagy/autophagy in primary human trabecular meshwork (hTM) cells. Trehalose, a natural disaccharide, activates autophagy and protects cells against environmental stresses. Here, we report that trehalose-induced autophagy enhanced outflow facility, reduced IOP, and protected against ocular hypertension in mice. We analyzed autophagy induction by trehalose in hTM cells. Our data demonstrated that trehalose transcriptionally upregulated prototypical autophagy related genes and activated autophagy through the downregulation of THBS1 . Consistent with prior findings, the results indicated that THBS1 silencing or inhibition is a key cellular event for the regulation of aqueous humor outflow and IOP homeostasis. In conclusion, this study identified trehalose-induced autophagy as a protective mechanism against ocular hypertension which may have therapeutic potential.

Age-related macular degeneration (AMD) is a degenerative eye disease leading to central vision loss and is characterized by dysregulated autophagy of the retinal pigment epithelium (RPE) layer. Recent studies have suggested that rho-associated protein kinase (ROCK) inhibitors may enhance autophagy in neurodegenerative diseases and promote the survival of RPE cells. This study investigated the effect of ROCK inhibitors on autophagy gene expression and autophagic vacuole formation in a human RPE (ARPE-19) cell line. The highly selective and potent ROCK inhibitor Y-39983 enhanced the expression of autophagy genes in ARPE-19 cells and increased autophagic vacuole formation. A proteomic analysis using mass spectrometry was performed to further characterize the effects of ROCK inhibition at the protein level. Y-39983 downregulated thrombospondin-1 (THBS1), and suppression of THBS1 in ARPE-19 cells resulted in an increase in autophagic vacuole formation. Our data showed that ROCK inhibitor-induced autophagy was mediated by THBS1 downregulation. We identified ROCK and THBS1 as potential novel therapeutic targets in AMD.