Transforming growth factor 2 (TGF2) signaling plays a key role in glucocorticoid-induced ocular hypertension

Ramesh B. Kasetti, Prabhavathi Maddineni, Pinkal D. Patel, Charles Searby, Val C. Sheffield, Gulab Zode

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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 (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. Dex also activated TGF2 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 TGF 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 TGF2 activation and ECM accumulation in TM cells. These observations suggested that chronic ER stress promotes Dex-induced ocular hypertension via TGF signaling. Our results indicate that TGF2 signaling plays a central role in GC-induced ocular hypertension and provides therapeutic targets for GC-induced ocular hypertension.

Original languageEnglish
Pages (from-to)9854-9868
Number of pages15
JournalJournal of Biological Chemistry
Volume293
Issue number25
DOIs
StatePublished - 1 Jan 2018

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Ocular Hypertension
Transforming Growth Factors
Dexamethasone
Glucocorticoids
Trabecular Meshwork
Endoplasmic Reticulum Stress
Extracellular Matrix
Intraocular Pressure
Activating Transcription Factor 4
Transcription Factor CHOP
Growth Factor Receptors
Aqueous Humor
Conditioned Culture Medium
Endoplasmic Reticulum
Phosphotransferases
Chemical activation
Therapeutics

Cite this

Kasetti, Ramesh B. ; Maddineni, Prabhavathi ; Patel, Pinkal D. ; Searby, Charles ; Sheffield, Val C. ; Zode, Gulab. / Transforming growth factor 2 (TGF2) signaling plays a key role in glucocorticoid-induced ocular hypertension. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 25. pp. 9854-9868.
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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 (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. Dex also activated TGF2 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 TGF 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 TGF2 activation and ECM accumulation in TM cells. These observations suggested that chronic ER stress promotes Dex-induced ocular hypertension via TGF signaling. Our results indicate that TGF2 signaling plays a central role in GC-induced ocular hypertension and provides therapeutic targets for GC-induced ocular hypertension.",
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Transforming growth factor 2 (TGF2) signaling plays a key role in glucocorticoid-induced ocular hypertension. / Kasetti, Ramesh B.; Maddineni, Prabhavathi; Patel, Pinkal D.; Searby, Charles; Sheffield, Val C.; Zode, Gulab.

In: Journal of Biological Chemistry, Vol. 293, No. 25, 01.01.2018, p. 9854-9868.

Research output: Contribution to journalArticleResearchpeer-review

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