Piezo1 activation induces fibronectin reduction and PGF2α secretion via arachidonic acid cascade

https://doi.org/10.1016/j.exer.2021.108917Get rights and content

Highlights

Piezo 1 agonist Yoda 1 enhanced the phosphorylation of cytosolic phospholipase A2 (cPLA2).

Piezo 1 agonist Yoda 1 enhanced the arachidonic acid cascade and increased MMP-2 expression.

Piezo 1 agonist Yoda 1 promoted the secretion of prostaglandin F2α (PGF2α) in HTMC.

Abstract

Glaucoma is a neurodegenerative disease that leads to blindness, and lowering intraocular pressure (IOP) is very important in glaucoma treatment. The trabecular meshwork is responsible for aqueous humor outflow, and the accumulation of fibronectin in trabecular meshwork is known to cause ocular hypertension. We have already shown that Piezo1 activation has an IOP lowering effect in mice and suppresses fibronectin expression level in human trabecular meshwork cells (HTMC). In this study, we report the mechanism of the reduction of fibronectin caused by Piezo1 activation. Activation of Piezo1 in HTMC showed increased expression of matrix metalloproteinase-2 (MMP-2) and cyclooxygenase (COX)-2, and decreased fibronectin expression. In addition, Piezo1 activation enhanced phosphorylation of cytosolic phospholipase A2 (cPLA2), and inhibitors targeting cPLA2 and COX-2 suppressed Yoda 1, a Piezo1 agonist, induced fibronectin reduction. These results indicate that the arachidonic acid cascade underlies this reaction, and, in support of this hypothesis, activation of Piezo1 promoted secretion of prostaglandin F2α (PGF2α) in HTMC. These results indicate that the activation of Piezo1 in HTMC promotes the degrading of fibronectin by promoting the arachidonic acid cascade and increasing the expression of PGF2α and MMP-2.

Keywords

Piezo1
Mechanosensitive channels
Trabecular meshwork
Glaucoma
cPLA2
MMP-2
ECM
Fibrosis

Abbreviations

IOP
intraocular pressure
HTMC
human trabecular meshwork cells
MMP-2
matrix metalloproteinase-2
COX
cyclooxygenase
cPLA2
cytosolic phospholipase A2
PGF2α
prostaglandin F2α
RGC
retinal ganglion cells
POAG
primary open-angle glaucoma
TMC
trabecular meshwork cells
ECM
extracellular matrix
LOX
lipoxygenase
LT
leukotriene
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