Abstract
Elevation of intraocular pressure (IOP) is a serious adverse effect of glucocorticoid (GC) therapy. Increased extracellular matrix (ECM) accumulation and endoplasmic reticulum (ER) stress in the trabecular meshwork (TM) is associated with GC-induced IOP elevation. However, the molecular mechanisms by which GCs induce ECM accumulation and ER stress in the TM have not been determined. Here, we show that a potent GC, dexamethasone (Dex), activates transforming growth factor β (TGFβ) signaling, leading to GC-induced ECM accumulation, ER stress, and IOP elevation. Dex increased both the precursor and bioactive forms of TGFβ2 in conditioned medium and activated TGFβ-induced SMAD signaling in primary human TM cells. Dex also activated TGFβ2 in the aqueous humor and TM of a mouse model of Dex-induced ocular hypertension. We further show that Smad3-/- mice are protected from Dex-induced ocular hypertension, ER stress, and ECM accumulation. Moreover, treating WT mice with a selective TGFβ receptor kinase I inhibitor, LY364947, significantly decreased Dex-induced ocular hypertension. Of note, knockdown of the ER stress-induced activating transcription factor 4 (ATF4), or C/EBP homologous protein (CHOP), completely prevented Dex-induced TGFβ2 activation and ECM accumulation in TM cells. These observations suggested that chronic ER stress promotes Dex-induced ocular hypertension via TGFβ signaling. Our results indicate that TGFβ2 signaling plays a central role in GC-induced ocular hypertension and provides therapeutic targets for GC-induced ocular hypertension.
Highlights
Elevation of intraocular pressure (IOP) is a serious adverse effect of glucocorticoid (GC) therapy
We hypothesized that Dex-induced extracellular matrix (ECM) accumulation and endoplasmic reticulum (ER) stress are regulated by transforming growth factor  (TGF)2 signaling
These data indicate that Dex increases secretion and activation of Transforming growth factor 2 (TGF2), which correlates with Dex-induced ECM and ER stress induction in human trabecular meshwork (TM) cells
Summary
Elevation of intraocular pressure (IOP) is a serious adverse effect of glucocorticoid (GC) therapy. We show that a potent GC, dexamethasone (Dex), activates transforming growth factor  (TGF) signaling, leading to GC-induced ECM accumulation, ER stress, and IOP elevation. Dex increased both the precursor and bioactive forms of TGF2 in conditioned medium and activated TGF-induced SMAD signaling in primary human TM cells. Knockdown of the ER stress–induced activating transcription factor 4 (ATF4), or C/EBP homologous protein (CHOP), completely prevented Dex-induced TGF2 activation and ECM accumulation in TM cells. These observations suggested that chronic ER stress promotes Dex-induced ocular hypertension via TGF signaling. Dex alters the expression of proteolytic enzymes, which regulate ECM turnover in the TM
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