Rapamycin protects glucocorticoid-induced glaucoma model mice against trabecular meshwork fibrosis by suppressing mTORC1/2 signaling.

Systemic or local use of glucocorticoids (GCs) can induce pathological elevation of intraocular pressure (IOP), potentially leading to permanent visual loss. Previous studies have demonstrated that rapamycin (Rapa) inhibits the activation of retinal glial cells and the production of neuroinflammation, achieving neuroprotective goals. However, there has been little research on the effect of Rapa on the trabecular meshwork (TM). This study aimed to investigate the protective effect and potential mechanism of Rapa in a glucocorticoid-induced glaucoma (GIG) model. Our findings indicate that Rapa significantly inhibited the IOP increase induced by dexamethasone acetate (Dex-Ac) and improved TM fibrosis and retinal ganglion cell (RGC) damage. In cultured human trabecular meshwork cells (HTMCs) treated with dexamethasone (Dex) and Rapa under different conditions revealed that Rapa inhibits Dex-induced HTMC fibrosis and cytoskeletal changes. This effect may result from the specific suppression of the mechanistic target of rapamycin complex 1 (mTORC1) pathway by Rapa, which reduces abnormal extracellular matrix (ECM) deposition. Alternatively, the improvement in cytoskeleton entanglement might be due to the inhibition of the mechanistic target of rapamycin complex2 (mTORC2) pathway. These two potential mechanisms may collectively contribute to the protective effects of Rapa in GIG. This study provides a new theoretical basis for using of Rapa in the treatment of GIG.