Intraocular pressure (IOP) rarely stands still. For many patients, it rises overnight – a clinically important fluctuation that can be missed by daytime measurements. Now, researchers have identified a molecular pathway that may help explain why this nighttime rise, pointing to a potential new target for glaucoma chronotherapy.

Writing in Communications Biology, the Japan-based team of researchers investigated how norepinephrine, a sympathetic neurotransmitter involved in circadian signaling, influences aqueous humor outflow through the trabecular meshwork (TM). Their experiments in human TM cells and mice centered on RHOB, a small GTPase that emerged from gene-expression analyses as a possible mediator of nocturnal IOP elevation.

The team first compared norepinephrine-induced gene-expression changes in mouse eyes and immortalized human TM cells. Eighteen genes were commonly upregulated, including RHOB. Further experiments showed that norepinephrine increased RHOB activity and expression through a β1-adrenergic receptor–cAMP–CREB signaling pathway.

So why might that matter for pressure control? The TM helps regulate conventional aqueous humor outflow, in part through phagocytosis that clears particulate material and debris from the drainage pathway. The researchers found that RHOB deficiency enhanced TM-cell phagocytosis, whereas RHOB overexpression suppressed it. RHOB overexpression also reduced permeability across multilayers of TM cells, while knocking out RHOB reversed the reduction in permeability caused by β1-adrenergic stimulation.

Taken together, the experiments support a model in which nocturnal norepinephrine activates β1-adrenergic signaling, increasing RHOB activity and suppressing TM phagocytosis. The resulting increase in aqueous outflow resistance may then contribute to higher nighttime IOP. The RHOB-dependent effects appeared strongest for phagocytosis, with smaller effects on other cellular behaviors such as adhesion and actin polymerization.

The investigators also tested the pathway pharmacologically in mice. RHO and ROCK inhibition suppressed nocturnal IOP elevation, while treatment with the β1-adrenergic agonist dobutamine increased IOP and this effect was prevented by RHO- or ROCK-pathway inhibition.

For glaucoma clinicians, the work adds mechanistic detail to an increasingly important question: how should treatment account for IOP outside office hours? Patients with glaucoma can experience nocturnal pressure elevations and altered circadian IOP patterns, meaning a seemingly satisfactory daytime reading may not necessarily capture the full pressure burden.

But RHOB remains a prospective therapeutic target rather than a clinical one. The study relied heavily on cultured TM cells and male mice, and the study authors note that circadian norepinephrine release from the superior cervical ganglion has not been clearly established in humans. Their initial mouse microarray analysis also used pooled RNA without biological replication.

Nevertheless, the findings raise the possibility: thatinstead of viewing IOP reduction solely in terms of how much pressure is lowered, future glaucoma therapy might also consider when specific molecular pathways are most active. Targeting RHOB – or related signaling upstream and downstream of it – could eventually offer a way to blunt the nocturnal pressure rise at its source.