Journal article
Transforming growth factor β2 (TGFβ2) signaling plays a key role in glucocorticoid-induced ocular hypertension
The Journal of biological chemistry, Vol.293(25), pp.9854-9868
06/2018
DOI: 10.1074/jbc.RA118.002540
PMCID: PMC6016452
PMID: 29743238
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.
Details
- Title: Subtitle
- Transforming growth factor β2 (TGFβ2) signaling plays a key role in glucocorticoid-induced ocular hypertension
- Creators
- Ramesh B Kasetti - Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas 76107Prabhavathi Maddineni - Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas 76107Pinkal D Patel - Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas 76107Charles Searby - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Val C Sheffield - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Gulab S Zode - Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas 76107
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.293(25), pp.9854-9868
- DOI
- 10.1074/jbc.RA118.002540
- PMID
- 29743238
- PMCID
- PMC6016452
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Grant note
- EY022077, EY026177, and EY024259 / National Institutes of Health
- Alternative title
- TGFβ signaling promotes GC-induced ocular hypertension
- Language
- English
- Date published
- 06/2018
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
- Record Identifier
- 9984070738802771
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