TRPV4 is activated by mechanical stimulation to induce prostaglandins release in trabecular meshwork, lowering intraocular pressure.

Autor: Uchida T; Department of Ophthalmology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.; Senju Laboratory of Ocular Science, Senju Pharmaceutical Co., Ltd., Kobe, Japan., Shimizu S; Department of Ophthalmology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.; Senju Laboratory of Ocular Science, Senju Pharmaceutical Co., Ltd., Kobe, Japan., Yamagishi R; Department of Ophthalmology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan., Tokuoka SM; Department of Lipidomics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan., Kita Y; Department of Lipidomics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.; Life Science Core Facility, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan., Sakata R; Department of Ophthalmology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan., Honjo M; Department of Ophthalmology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan., Aihara M; Department of Ophthalmology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2021 Oct 21; Vol. 16 (10), pp. e0258911. Date of Electronic Publication: 2021 Oct 21 (Print Publication: 2021).
DOI: 10.1371/journal.pone.0258911
Abstrakt: Trabecular meshwork constitutes the conventional outflow pathway and controls intraocular pressure by regulating aqueous outflow. Mechanical stimulation has been studied as one of the triggers to regulate aqueous outflow in trabecular meshwork, but it is not well understood. We investigated that how transient receptor potential cation channel subfamily V member 4 (TRPV4) functions in human trabecular meshwork cells (HTMC) and affects intraocular pressure (IOP). HTMC were treated with TRPV4 siRNA, followed by incubation for 24 hours. We confirmed the suppression of TRPV4 mRNA expression and the reduction of Ca2+ influx by the TRPV4 agonist GSK1016790A in TRPV4 siRNA-treated HTMC. TRPV4 siRNA-treated HTMC exhibited a significant reduction in Ca2+ influx and production of arachidonic acid and prostaglandin (PG) E2 induced by mechanical stretch, and direct activation of TRPV4 by GSK1016790A increased production of arachidonic acid, PGE2, and PGD2 and inhibited gel contraction. Furthermore, TRPV4-deficient mice had higher IOP than wild-type mice, and GSK1016790A administration lowered IOP. These results suggest that TRPV4 mediates the cellular response induced by trabecular meshwork stretch, leading to IOP reduction through the production of prostaglandins and inhibition of cell contraction. Targeting TRPV4 may have therapeutic benefits that lead to lowering IOP in glaucoma patients.
Competing Interests: Takatoshi Uchida and Shota Shimizu are employees of the Senju Pharmaceutical Co.,Ltd. The other authors declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Databáze: MEDLINE
Externí odkaz: