Abstract
The trabecular meshwork (TM) constitutes the main pathway for aqueous humor drainage and is exposed to complex intraocular pressure fluctuations. The mechanism of homeostasis in which TM senses changes in intraocular pressure and leads to normal levels of outflow resistance is not yet well understood. Previous reports have shown that Piezo1, a mechanically-activated cation channel, is expressed in TM and isolated TM cells. Therefore, we tested hypothesis that Piezo1 may function in response to membrane tension and stretch in TM. In human trabecular meshwork (hTM) cells, PIEZO1 was showed to be abundantly expressed, and Piezo1 agonist Yoda1 and mechanical stretch caused a Piezo1-dependent Ca2+ influx and release of arachidonic acid and PGE2. Treatment with Yoda1 or PGE2 significantly inhibited hTM cell contraction. These results suggest that mechanical stretch stimuli in TM activates Piezo1 and subsequently regulates TM cell contraction by triggering Ca2+ influx and release of arachidonic acid and PGE2. Thus, Piezo1 could acts as a regulator of intraocular pressure (IOP) within the conventional outflow pathway and could be a novel therapeutic strategy to modulate IOP in glaucoma patients.
Highlights
Intraocular pressure (IOP) is regulated by the production and outflow of aqueous humor and has been associated with increased risk of glaucoma development
We found that mechanical stretch stimulation significantly increased the amounts of arachidonic acid and PGE2 released from human trabecular meshwork (hTM) cells (Fig. 4A,B)
We analyzed the expression of TRPV1-6 and PIEZO1-2 in hTM cells and found that Piezo[1] was most abundantly expressed at the mRNA level
Summary
Intraocular pressure (IOP) is regulated by the production and outflow of aqueous humor and has been associated with increased risk of glaucoma development. In response to mechanical stretch or strain, TM cells activate intracellular signaling pathways leading to changes in gene expression, extracellular matrix (ECM) turnover, contractile p roperties[2,6]. The non-selective cation channel TRPV4 and the two-pore domain potassium channel TREK1 are expressed in TM cells, sense mechanical stretch generated by fluctuations in IOP, and play an essential role in IOP adjustment[7,8,9,10]. We hypothesized that in TM, Piezo[1] might respond to mechanical stress and regulate IOP by locally releasing lipid mediators. We investigated the involvement of Piezo[1] on the mechanical stress and the release of lipid mediators in primary cultured human TM cells
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