Fluvoxamine supresses transforming growth factor beta‐2‐induced fibrotic changes in trabecular meshwork cells.

Aims/Purpose: Primary open‐angle glaucoma is the leading cause of blindness worldwide, but no definitive treatment is available. Fibrotic‐like changes of trabecular meshwork (TM) results in increased stiffness and impaired outflow leading to increased IOP. Transforming growth factor‐β2 (TGF‐β2), a main driver of eye fibrosis, is increased in the aqueous humour of glaucoma patients. Recently, we proved that the specific sigma‐1 receptor agonist fluvoxamine (FLU) is antifibrotic in the kidney but its role in the TM is unknown. Therefore, we investigated the effects of FLU on the TGF‐β2‐induced fibrotic response in TM cells. Methods: Fibrosis of the AS was induced in C57BL/6J mice by intracameral TGF‐β2 injection. AS were collected and F‐actin was visualized with Phalloidin and detected with confocal microscopy. The effect of FLU on TGF‐β2‐induced cell proliferation, cytoskeletal rearrangement, and fibrosis‐related proteins was investigated by MTT (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5 diphenyl tetrazolium bromide) assay, Phalloidin staining and Western blotting, respectively. Results: TGF‐β2 injection resulted in F‐actin enhancement in vivo, indicating fibrotic‐like changes. In vitro, TGF‐β2 induced cytoskeletal rearrangement with increased F‐actin‐ bundles and clumps formation (p < 0.001) which were reduced by FLU (p < 0.001). Furthermore, FLU also inhibited cell proliferation (p < 0.05) in TGF‐β2‐treated cells. The profibrotic protein levels of connective tissue growth factor, fibronectin and collagen type IV were elevated by TGF‐β2 treatment (p < 0.001), while FLU prevented the elevation of these elements (p < 0.01; p < 0.001). FLU also hindered the TGF‐β2 caused decrease of Matrix Metalloproteinase‐2 (p < 0.05) thus facilitating ECM degradation. Conclusions: FLU may reduce the fibrotic response of trabecular meshwork and could be a potential candidate for the treatment of fibrosis‐induced ocular hypertension. Grants: OTKA‐ K135398, LP2021‐3/2021, TKP2021‐EGA‐24, Stipendium Hungaricum. [ABSTRACT FROM AUTHOR]