Abstract
We examined the effects of mTOR inhibitors on the fibrotic response induced by transforming growth factor-beta2 (TGF-β2) in cultured human trabecular meshwork (hTM) cells. TGF-β2-induced expression of fibronectin, collagen type I, alpha 1 chain (COL1A1), and alpha-smooth muscle actin (αSMA) in hTM cells was examined in the presence or absence of mTOR inhibitors using quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. The migration rates of hTM cells were examined in the presence of TGF-β2 with or without mTOR inhibitors. An in vitro study showed that the expression of fibronectin, COL1A1, and αSMA was upregulated by TGF-β2 treatment of hTM cells; such upregulation was significantly suppressed by mTOR inhibitors. The inhibitors significantly reduced the migration rate of TGF-β2-stimulated hTM cells. mTOR inhibitors may usefully reduce the fibrotic response of hTM cells and we may have to explore if it is also effective in in vivo model.
Highlights
Glaucoma is known to be the second leading cause of blindness worldwide
We explored whether Mammalian target of rapamycin (mTOR) inhibitors reduced extracellular matrix (ECM) remodeling and TM cell fibrosis, both of which are thought to play roles in the pathogenesis of glaucoma
Many soluble mediators affect ECM remodeling and TM fibrosis; in particular, elevated levels of TGF-β2 play a critical role in glaucoma pathogenesis
Summary
Glaucoma is known to be the second leading cause of blindness worldwide. Aberrant increases in intraocular pressure (IOP) characterize glaucoma, and such an increase in IOP can damage the optic n erve[1,2,3]. Various aqueous soluble mediators (i.e. vascular endothelial growth factor (VEGF), connective tissue growth factor (CTGF), transforming growth factor-beta (TGF-β), monocyte chemotactic protein-1 (MCP-1), and members of the matrix metalloproteinase (MMP) family), are reported to have important roles in the ECM production and induction of fibrogenic changes in human trabecular meshwork (hTM) cells. The PI3K/mTOR pathway has been implicated in initiating fibroblast proliferation, survival and differentiation. In fibroblasts derived from lung or hepatic fibrosis patients’ tissue, they are known to show aberrant PI3K a ctivity[18,19,20,21]. PI3K-mTOR pathway could be involved in fibrotic changes in glaucomatous lamina cribrosa cells. Given the role of TM’s profibrotic changes in contributing to elevated intraocular pressure, this study investigated whether TGF-β2-PI3K-mTOR pathway is involved in hTM cell profibrosis’. We evaluated if mTOR inhibitors might attenuate hTM cells’ fibrosis induced by TGF-β2 in vitro
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