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.
Highlights
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
In order to gain more insight in the role of dysregulated autophagy in the TM pathophysiology and glaucoma, we have explored the effects of downregulating autophagy on TM cell function
We shall highlight the upregulated expression of transforming growth factor-β2 (TGFβ2) (2.04 fold, p = 0.02) and its pseudoreceptor BMP and activin membrane bound inhibitor (BAMBI) genes (2.17 fold, p = 0.008), as well as the downregulation of the fibrotic marker α-smooth muscle actin (SMA, −1.56 fold, p = 0.003, Table S2) in autophagy-deficient TM cells
Summary
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. The functional decline of this tissue, in particular with aging, causes elevation in IOP This increases the risk of developing glaucoma, the second leading cause of blindness worldwide[1]. Several morphological changes have been described in the TM from glaucoma patients in comparison to age-matched controls These include decrease in cellularity, abnormal accumulation of extracellular matrix (ECM) and thickening of the trabecular beams[2,3]. Our results indicate a cross-talk between autophagy and TGFβ signaling pathway, and a role of autophagy in regulating fibrosis in TM cells
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