Dexamethasone induces trabecular meshwork cell myofibroblast transdifferentiation through ARHGEF26

Area of Science:

• Ophthalmology
• Cell Biology
• Pharmacology

Background:

• Glucocorticoid use is linked to elevated intraocular pressure and glaucoma.
• The precise mechanisms driving glucocorticoid-induced glaucoma (GIG) are not fully understood.

Purpose of the Study:

• To investigate the role of dexamethasone-induced myofibroblast transdifferentiation in trabecular meshwork cells (TMCs) in GIG pathogenesis.
• To explore the potential therapeutic effect of inhibiting Rho guanine nucleotide exchange factor 26 (ARHGEF26) in GIG.

Main Methods:

• Primary human TMCs and mice were treated with dexamethasone.
• ARHGEF26 expression was knocked down in cellular and animal models.
• Changes in cell morphology, cytoskeletal organization, myofibroblast markers, extracellular matrix deposition, and cellular function were assessed.
• Intraocular pressure was monitored in mice.

Main Results:

• Dexamethasone induced myofibroblast transdifferentiation in TMCs, characterized by cytoskeletal changes, altered morphology, increased matrix deposition, and dysfunction.
• ARHGEF26 knockdown ameliorated dexamethasone-induced changes and prevented intraocular hypertension in mice.
• The observed effects may involve the TGF-β pathway.

Conclusions:

• Glucocorticoids induce myofibroblast transdifferentiation in TMCs, a key factor in GIG development.
• Inhibiting ARHGEF26 protects TMCs by reversing myofibroblast transdifferentiation.
• Reversing TMC myofibroblast transdifferentiation presents a novel therapeutic target for GIG.