Norepinephrine-induced small GTPase RHOB mediates nocturnal intraocular pressure rise in mice

Intraocular pressure (IOP), a major risk factor for glaucoma, follows a circadian rhythm with nocturnal increases driven by norepinephrine (NE) from the superior cervical ganglion. This rhythm depends on aqueous humor (AH) dynamics, particularly the outflow through the trabecular meshwork (TM). Herein, we investigated its underlying regulatory mechanisms in the TM because disruption of IOP rhythm increases the risk of glaucoma. Comprehensive gene expression analysis of human TM cells and mouse eyes uncovered NE-upregulated 18 genes, including the small GTPase RHOB. Promoter assays revealed that RHOB is regulated via a cAMP-responsive element. RHOB deficiency enhanced TM phagocytosis and reversed NE-induced suppression of permeability, whereas RHOB overexpression had the opposite effect. In mice, RHO and ROCK inhibitors reduced both nocturnal and NE-induced IOP elevations. These findings suggest that NE elevates IOP by inhibiting TM phagocytosis via RHOB, identifying RHOB as a key regulator of IOP rhythm and a potential target for glaucoma treatment.