Molecular Mechanisms of Sympathetic Circadian IOP Regulation in the Trabecular Meshwork

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Summary of  Communications Biology. https://doi.org/10.1038/s42003-026-10710-1  
Dr. Keisuke Ikegami  et al.

Points

Kyushu University researchers identified a molecular pathway in the trabecular meshwork explaining why intraocular pressure increases during nocturnal hours.
Sympathetic release of norepinephrine upregulates the small GTPase RHOB across a panel of eighteen responsive ocular drainage genes.
Increased RHOB levels suppress phagocytic waste clearance and decrease aqueous humor permeability within human trabecular meshwork cells.
Murine experiments demonstrated that topical RHO and ROCK inhibitors effectively suppress both norepinephrine-induced and nocturnal eye pressure spikes.
Targeted chronotherapy against the RHOB pathway offers potential to control circadian intraocular pressure fluctuations and enhance early glaucoma interventions.

Summary

This study evaluated the molecular mechanisms governing nocturnal intraocular pressure (IOP) elevation in the trabecular meshwork (TM) driven by sympathetic norepinephrine (NE) release from the superior cervical ganglion. Intraocular pressure follows a diurnal circadian rhythm with nighttime spikes, representing a major risk factor for glaucoma progression that is often undetected during daytime clinical evaluations. Led by Keisuke Ikegami at Kyushu University and published in Communications Biology, the research sought to identify NE-upregulated genetic targets that impair trabecular meshwork aqueous humor (AH) drainage and cellular clearance functions.

Comprehensive gene expression profiling in human TM cells and murine ocular tissues identified 18 genes consistently upregulated following NE exposure. Promoter assays demonstrated that expression of the small GTPase RHOB is directly regulated via a cAMP-responsive element. Functional assays revealed that RHOB expression inhibits TM cellular phagocytosis and suppresses tissue permeability. Conversely, RHOB knockout enhanced phagocytic waste clearance and restored outflow facility, demonstrating that NE elevates IOP by impeding the physiological cleaning capacity of the trabecular meshwork via RHOB signaling.

In vivo murine experiments evaluated the therapeutic efficacy of targeting the RHO-ROCK signaling cascade to attenuate circadian IOP fluctuations. Administration of topical RHO and ROCK inhibitor eye drops successfully blunted both NE-induced and physiological nocturnal IOP spikes. The authors conclude that RHOB serves as a master molecular regulator of circadian IOP dynamics, highlighting RHO-ROCK pathway inhibition as a targeted chronotherapeutic strategy to mitigate nocturnal IOP elevations and improve longitudinal glaucoma management.

Link to the article: https://www.nature.com/articles/s42003-026-10710-1

References

Ikegami, K., Takahashi, T., Katamoto, Y., Oishi, A., Yoshimi, A., Nagase, M., Miki, A., Yasuo, S., & Masubuchi, S. (2026). Norepinephrine-induced small GTPase RHOB mediates nocturnal intraocular pressure rise in mice. Communications Biology. https://doi.org/10.1038/s42003-026-10710-1