Objective:

Investigate how norepinephrine signaling affects trabecular meshwork function and may contribute to nocturnal intraocular pressure (IOP) elevation.

Approach:

• Gene-expression analysis: Compared norepinephrine-induced gene-expression changes in mouse eyes and immortalized human trabecular meshwork (TM) cells.
• Cell experiments: Examined RHOB signaling, TM-cell phagocytosis, and permeability after RHOB manipulation and β1-adrenergic stimulation.
• Mouse experiments: Tested the effects of RHO/ROCK-pathway inhibition and the β1-adrenergic agonist dobutamine on IOP.

Key Findings:

• Eighteen genes were commonly upregulated by norepinephrine in mouse eyes and human TM cells, including RHOB.
• Norepinephrine increased RHOB activity and expression through a β1-adrenergic receptor–cAMP–CREB pathway.
• RHOB deficiency enhanced TM-cell phagocytosis, while RHOB overexpression suppressed phagocytosis and reduced permeability across TM-cell layers.
• RHO and ROCK inhibition suppressed nocturnal IOP elevation in mice; dobutamine increased IOP, and this effect was prevented by RHO- or ROCK-pathway inhibition.

Interpretation:

The experiments support a model in which nocturnal norepinephrine signaling increases RHOB activity, suppresses TM phagocytosis, and may increase aqueous outflow resistance and nighttime IOP. RHOB-dependent effects were strongest for phagocytosis.

Limitations:

• The study relied heavily on cultured TM cells and male mice.
• Circadian norepinephrine release from the superior cervical ganglion has not been clearly established in humans.
• The initial mouse microarray analysis used pooled RNA without biological replication.

Conclusion:

RHOB and related signaling pathways are prospective targets for studying nocturnal IOP elevation; the findings do not establish a clinical treatment.

Sources:

• Article context supplied by the user