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J Biol Chem. 2018 Jun 22;293(25):9854-9868. doi: 10.1074/jbc.RA118.002540. Epub 2018 May 9.

Transforming growth factor β2 (TGFβ2) signaling plays a key role in glucocorticoid-induced ocular hypertension.

Author information

1
From the Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas 76107 and.
2
the Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242.
3
From the Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas 76107 and gulab.zode@unthsc.edu.

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.

KEYWORDS:

SMAD transcription factor; endoplasmic reticulum stress (ER stress); extracellular matrix (ECM) protein; glucocorticoid; glucocorticoids; growth factor; ocular hypertension; steroid-induced glaucoma; trabecular meshwork; transforming growth factor β2 (TGFβ2)

PMID:
29743238
PMCID:
PMC6016452
[Available on 2019-06-22]
DOI:
10.1074/jbc.RA118.002540
[Indexed for MEDLINE]

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