June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Inhibition of Transforming Growth Factor-β2 Signaling Prevents ECM Remodeling, Endoplasmic Reticulum Stress and Ocular Hypertension in Steroid-induced Glaucoma
Author Affiliations & Notes
  • Ramesh Kasetti
    North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas, United States
  • Prabhavathi Maddineni
    North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas, United States
  • Pinkal Patel
    North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas, United States
  • J Cameron Millar
    North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas, United States
  • Tien Phan
    North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas, United States
  • Charles C Searby
    Department of Pediatrics, University of Iowa, Iowa city, Iowa, United States
  • Abbot F Clark
    North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas, United States
  • Val Sheffield
    Department of Pediatrics, University of Iowa, Iowa city, Iowa, United States
  • Gulab Zode
    North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas, United States
  • Footnotes
    Commercial Relationships   Ramesh Kasetti, None; Prabhavathi Maddineni, None; Pinkal Patel, None; J Cameron Millar, None; Tien Phan, None; Charles Searby, None; Abbot Clark, None; Val Sheffield, None; Gulab Zode, None
  • Footnotes
    Support  EY026177
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4603. doi:
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      Ramesh Kasetti, Prabhavathi Maddineni, Pinkal Patel, J Cameron Millar, Tien Phan, Charles C Searby, Abbot F Clark, Val Sheffield, Gulab Zode; Inhibition of Transforming Growth Factor-β2 Signaling Prevents ECM Remodeling, Endoplasmic Reticulum Stress and Ocular Hypertension in Steroid-induced Glaucoma. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4603.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Ocular hypertension is a serious side effect of glucocorticoid (GC) therapy. Abnormal accumulation of extracellular matrix (ECM) and chronic endoplasmic reticulum (ER) stress in the trabecular meshwork (TM) is associated with GC-induced ocular hypertension. In the present study, we examined the role of TGFβ2 signaling in dexamethasone (Dex)-induced ECM remodeling, ER stress and ocular hypertension

Methods : Conscious IOP and outflow facility was measured in C57 mice treated with vehicle or Dex eye drops up to 7-weeks. TGFβ2 & fibronectin levels in the aqueous humor (AH) were analyzed by Western. Effect of inhibition of TGFβ signaling on Dex-induced ER stress and ECM accumulation was examined by Western blot, immunostaining & Smad reporter assay in TM cells treated with or without TGFβ signaling inhibitors (SIS3 and LY364947). To further examine the role of TGF-β2 signaling, IOP, ECM and ER stress was examined in WT or Smad3-/- mice treated with Dex

Results : Dexamethasone (Dex) mediated reduction of outflow facility and IOP elevation is associated with increased abnormal extracellular matrix (ECM) accumulation in the TM, inducing ER stress. Biochemical analysis of the aqueous humor samples from Dex-treated eyes revealed significantly increased bioactive form of transforming growth factor-β2 (TGF-β2), a major regulator of ECM in the TM. Dex treatment increased both precursor and bioactive form of TGF-β2 in the conditioned medium and activated TGF-β2-induced Smad signaling pathway in primary human TM cells as evident from increased phosphorylation of Smad3 and increased Smad luciferase activity. Inhibition of TGF-β2 signaling significantly reduced Dex-induced abnormal intracellular ECM accumulation and ER stress in human TM cells. Smad3-/- mice, which are required for TGF-β2 signaling, protected from Dex-induced ocular hypertension, ER stress and abnormal ECM accumulation further indicating the role of TGF-β2 signaling in GC-induced glaucoma. Interestingly, knock out of ER stress-induced transcriptional factors, ATF4 and CHOP prevented activation of TGF-β2 signaling and also reduced intracellular ECM accumulation in the TM, thus preventing Dex-induced ER stress and IOP elevation

Conclusions : These studies indicate that Dex-induced TGF-β2 signaling is responsible for ECM remodeling, ER stress and elevation of IOP in GC-induced glaucoma

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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