New mechanism behind nighttime eye pressure spikes linked to glaucoma

Intraocular pressure is the most important risk factor involved in the onset and progression of glaucoma. This pressure fluctuates throughout the day and is known to become high at night in both humans and mice. However, the molecular mechanisms by which reduced drainage of aqueous humor, the fluid inside the eye, contributes to nighttime increases in intraocular pressure have remained unclear.

A research group including Associate Professor Keisuke Ikegami at the Faculty of Agriculture, Kyushu University, through research advanced since his tenure at Aichi Medical University, found that noradrenaline released by sympathetic nerves increases levels of the small GTPase RHOB in the trabecular meshwork, the eye's primary drainage tissue. Increased RHOB levels appear to impair the ability of trabecular meshwork cells to engulf and process waste material, potentially reducing aqueous humor drainage. This could help guide chronotherapy approaches that optimize the timing of glaucoma treatment and support the development of new strategies that target RHOB to regulate intraocular pressure rhythms. The findings were published in Communications Biology.

The group previously reported that noradrenaline released from sympathetic nerves contributes to nighttime increases in intraocular pressure in mice. On the other hand, details such as how noradrenaline alters cellular functions of the trabecular meshwork and lowers aqueous humor discharge were unclear.

Trabecular meshwork cells possess a phagocytic function that allows them to engulf and process waste material and microscopic particles in the aqueous humor. This function is considered important for keeping drainage pathways of the eye clean and maintaining the flow of aqueous humor. Therefore, they focused on the effects of noradrenaline on gene expression and phagocytic function of trabecular meshwork cells.

The research group first comprehensively analyzed gene expression using eyes of mice administered noradrenaline and human trabecular meshwork cells stimulated with noradrenaline. The analysis identified 18 genes that were upregulated in both systems. Among these 18 genes, the research group focused on small G-protein RHOB. RHOB is a small signaling protein involved in regulating cell shape, movement, and intracellular trafficking. It was found that expression and activity of RHOB rise in human trabecular meshwork cells through noradrenaline stimulation.

Next, they investigated how RHOB increases. Noradrenaline increases cAMP via β1-adrenergic receptors. In the study, they showed that transcription factor CREB responding to cAMP acts on highly conserved sequences located near the RHOB gene, thereby elevating expression of RHOB.

Furthermore, to investigate actions of RHOB, they generated human trabecular meshwork cells deficient in RHOB. Loss of RHOB enhanced the phagocytic activity of trabecular meshwork cells. On the other hand, when overexpressing RHOB, phagocytic function lowered, and permeability of fluid passing through layers of trabecular meshwork cells also lowered. These findings suggest that RHOB may act to impede aqueous humor outflow.

In eye drop experiments using mice, when administering RHO inhibitors or ROCK inhibitors, nocturnal intraocular pressure elevation was suppressed. In control mice, the difference between daytime and nighttime intraocular pressure was approximately 4 mmHg. Treatment with either inhibitor significantly reduced this nighttime increase. In addition, intraocular pressure elevation via β1-adrenergic receptor agonists mimicking actions of noradrenaline was also suppressed by RHO/ROCK inhibition.

From these results, it was shown that sympathetic signals strengthening at night increase RHOB in the trabecular meshwork and weaken aqueous humor discharge functions centering on phagocytosis, thereby contributing to nocturnal intraocular pressure elevation.

While the present study is basic research using mice and human trabecular meshwork cells, it presented the RHOB pathway as a new target to suppress nocturnal intraocular pressure elevation. While ROCK inhibitors are already used as glaucoma therapeutics, during which time band administration is most effective and how intraocular pressure rhythms are altered require further verification in the future. It becomes a foundation to consider therapeutic strategies focusing on time bands where nocturnal sympathetic signals are strong.

In the future, the research group aims to verify relationships among nocturnal intraocular pressure fluctuations, sympathetic nerve activity, and trabecular meshwork functions in humans, optimizing therapeutic timing according to intraocular pressure rhythms for each patient. In addition, they will explore possibilities of new therapeutic methods targeting RHOB itself or molecules controlling RHOB. In the future, risk evaluation of nocturnal intraocular pressure elevation overlooked solely by daytime intraocular pressure measurements and contribution to chronomedicine for glaucoma therapeutics are expected.

Ikegami commented, "Intraocular pressure changes significantly within a day. This time, as a mechanism where intraocular pressure rises at night, we found a molecular pathway where sympathetic nerves alter cellular functions of drainage pathways of the eye. We wish to understand risks of glaucoma onset and progression on a time axis, leading to proposals of more appropriate therapeutic timings."

Journal Information
Publication: Communications Biology
Title: Norepinephrine-induced small GTPase RHOB mediates nocturnal intraocular pressure rise in mice
DOI: 10.1038/s42003-026-10710-1