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Abstract #77060 Published in IGR 19-3
Transforming growth factor β2 (TGFβ2) signaling plays a key role in glucocorticoid-induced ocular hypertension
Kasetti RB; Maddineni P; Patel PD; Searby C; Sheffield VC; Zode GSJournal of Biological Chemistry 2018; 293: 9854-9868
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 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.
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.
Full articleClassification:
9.4.1 Steroid-induced glaucoma (Part of: 9 Clinical forms of glaucomas > 9.4 Glaucomas associated with other ocular and systemic disorders)
3.6 Cellular biology (Part of: 3 Laboratory methods)
2.5.1 Trabecular meshwork (Part of: 2 Anatomical structures in glaucoma > 2.5 Meshwork)
