Literature Interpretation: Mechanical Force and Glucocorticoid-Sensitive TREK-1 Channels Regulate Conventional Aqueous Humor Outflow and Intraocular Pressure
Release time:
2026-08-13
Research Background:
Glucocorticoids are widely used clinically to treat autoimmune diseases, ocular disorders (Graves' ophthalmopathy, uveitis), allergies, asthma, heart failure, skin diseases, and postoperative inflammation. Glucocorticoids can elevate intraocular pressure (IOP) by increasing outflow resistance through the conventional aqueous humor outflow pathway. This study aimed to investigate two aspects: to identify the molecular link between glucocorticoid exposure and mechanosensation, and to elucidate the role of the mechanosensitive TWIK-related potassium channel 1 (TREK‑1) in regulating aqueous humor outflow and glucocorticoid-induced ocular hypertension (OHT).
Research Methods:
Real-time quantitative PCR (Real-time PCR) was used to examine whether the expression of genes encoding two-pore-domain potassium (K2P) channels, transient receptor potential vanilloid (TRPV) channels, Piezo channels, extracellular matrix (ECM) components, and fibrosis markers in mouse trabecular meshwork (mTM) cells is regulated by the corticosteroid dexamethasone (DEX).
Immunohistochemistry was performed to localize TREK‑1. The iPerfusion system was used to assess whether conventional aqueous humor outflow depends on TREK‑1. Mouse intraocular pressure (IOP) was monitored using the Tonolab rebound tonometer (Icare Finland Oy, Helsinki, Finland) specifically designed for mice and rats, and telemetry was further employed to verify whether ocular hypertension (OHT) in rats is TREK‑1 dependent.
Whole-cell recordings were performed in primary human trabecular meshwork (TM) cells to validate the transcriptional inhibitory effect of glucocorticoids on the Kcnk2 gene in mouse trabecular meshwork cells.
Research Results:
In the two-pore-domain potassium channel transcriptome of mouse trabecular meshwork (mTM) cells, Trek-1 (Kcnk2) mRNA was absolutely predominant, while minor transcripts of Traak and Thik-2, as well as low levels of Trek-2, Twik3, and Task1, were also detected.
Dexamethasone (DEX) upregulated Fsp1 and suppressed Kcnk2 expression, but did not affect the mRNA levels of Trpv4, Piezo1, or Trpc1.
The TREK‑1 agonist ML‑402 doubled aqueous humor facility in mouse eyes and reduced IOP in both the DEX-induced mouse ocular hypertension model and spontaneously hypertensive rats.
Chronic DEX exposure caused depolarization of primary human trabecular meshwork (pTM) cells and reduced the amplitude of ML‑402-evoked currents.
Research Conclusion:
Excessive ocular exposure to glucocorticoids may disrupt IOP homeostasis by impairing the expression and function of TREK‑1 in the trabecular meshwork. Pharmacological activation of TREK‑1 facilitates conventional aqueous humor outflow and holds promise for lowering IOP in patients with glucocorticoid-induced ocular hypertension.
Publication Information:
Authors:
Sarah N. Redmon; Oleg Yarishkin; Christopher N. Rudzitis; Monika Lakk; Jacques Bertrand; Joseph van Batenburg-Sherwood; Christina M. Nicou; Christopher L. Passaglia; Darryl R. Overby; David Križaj
Journal:
Investigative Ophthalmology & Visual Science
November 2025, Vol.66, 57
doi:https://doi.org/10.1167/iovs.66.14.57
Semantic Scholar：https://iovs.arvojournals.org/article.aspx?articleid=2811136&resultClick=1
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