MRP4-Mediated Regulation of Intracellular cAMP and cGMP Levels in Trabecular Meshwork Cells and Homeostasis of Intraocular Pressure

Abstract The trabecular meshwork (TM) is a specialized ocular tissue, which is responsible, together with the Schlemm’s canal (SC), for maintaining appropriate levels of intraocular pressure. Dysfunction of these tissues leads to ocular hypertension and increases the risk for developing glaucoma. Previous work by our laboratory revealed dysregulated autophagy in aging and in glaucomatous TM cells. In order to gain more insight in the role of autophagy in the TM pathophysiology, we have conducted transcriptome and functional network analyses of TM primary cells with silenced expression of the autophagy genes Atg5 and Atg7. Atg5/7-deficient TM cells showed changes in transcript levels of several fibrotic genes, including TGFβ2, BAMBI, and SMA. Furthermore, genetic and pharmacological inhibition of autophagy was associated with a parallel reduction in TGFβ-induced fibrosis, caused by a BAMBI-mediated reduced activation of Smad2/3 signaling in autophagy-deficient cells. At the same time, TGFβ treatment led to Smad2/3-dependent dysregulation of autophagy in TM cells, characterized by increased LC3-II levels and autophagic vacuoles content. Together, our results indicate a cross-talk between autophagy and TGFβ signaling in TM cells.

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Mechanical stretch induces Ca2+ influx and extracellular release of PGE2 through Piezo1 activation in trabecular meshwork cells

Scientific Reports ◽

10.1038/s41598-021-83713-z ◽

2021 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Takatoshi Uchida ◽

Shota Shimizu ◽

Reiko Yamagishi ◽

Suzumi M. Tokuoka ◽

Yoshihiro Kita ◽

...

Keyword(s):

Arachidonic Acid ◽

Intraocular Pressure ◽

Trabecular Meshwork ◽

Pressure Fluctuations ◽

Mechanical Stretch ◽

Cell Contraction ◽

Trabecular Meshwork Cells ◽

Extracellular Release ◽

Main Pathway ◽

Outflow Pathway

AbstractThe 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.

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New Insights Into Pathophysiological Mechanisms Regulating Conventional Aqueous Humor Outflow

Medicina ◽

10.3390/medicina49040026 ◽

2013 ◽

Vol 49 (4) ◽

pp. 26 ◽

Cited By ~ 2

Author(s):

Daiva Paulavičiūtė-Baikštienė ◽

Rūta Baršauskaitė ◽

Ingrida Janulevičienė

Keyword(s):

Intraocular Pressure ◽

Aqueous Humor ◽

Trabecular Meshwork ◽

Kinase Inhibitors ◽

Transforming Growth Factor ◽

Protein Kinase Inhibitors ◽

Pathophysiological Mechanisms ◽

Aqueous Humor Outflow ◽

Trabecular Meshwork Cells ◽

Glaucoma Treatment

The aim of the article was to overview the pathophysiology of the conventional outflow pathway, trabecular meshwork, and intraocular pressure and to discuss the options of future glaucoma treatment directed to improvement in aqueous outflow. The literature search in the Medline, Embase, and Cochrane databases from April to May 2012 was performed; a total of 47 articles analyzed. The diminished conventional pathway may be altered by several pathophysiological mechanisms like TM obstruction caused by transforming growth factor-β2, clastic nondeformable cells, macrophages leaking from hypermature cataract, iris pigment, lens capsular fragments after YAG-laser posterior capsulotomy, proteins and their subfragments. It is known that trabecular meshwork contraction reduces outflow, and the actomyosin system is directly linked to this mechanism. New glaucoma drugs are still under investigation, but it is already proven that agents such as latranculin-B are effective in improving aqueous drainage. Selective Rho-associated coiled coilforming protein kinase inhibitors have been shown to cause a significant improvement in outflow facility and may become a new option for glaucoma treatment. Caldesmon negatively regulates actin-myosin interactions and thus increases outflow. Stem cells may replace missing or nonfunctional trabecular meshwork cells and hopefully will bring a new treatment solution. Pathophysiological mechanisms regulating conventional aqueous humor outflow are still not fully understood and require further investigations. Future treatment decisions should be directed to a specific mechanism regulating an elevation in intraocular pressure.

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