June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
The Retinal Pigment Epithelium has increased oxidative stress and is more susceptible to oxidative stress-induced degeneration in Sorsby Fundus Dystrophy
Author Affiliations & Notes
  • Alyson Wolk
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
    Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, United States
  • Mala Upadhyay
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
  • Mariya Ali
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
  • Jason Suh
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
  • Julia C Batoki
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
  • Rupesh Singh
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
  • Vera L Bonilha
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
  • Bela Anand-Apte
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
    Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, United States
  • Footnotes
    Commercial Relationships   Alyson Wolk, None; Mala Upadhyay, None; Mariya Ali, None; Jason Suh, None; Julia Batoki, None; Rupesh Singh, None; Vera Bonilha, None; Bela Anand-Apte, None
  • Footnotes
    Support  T32EY024236, P30 EY025585. RO1EY026181, RO1 EY027083, RPB Unrestricted Grant
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 4163. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Alyson Wolk, Mala Upadhyay, Mariya Ali, Jason Suh, Julia C Batoki, Rupesh Singh, Vera L Bonilha, Bela Anand-Apte; The Retinal Pigment Epithelium has increased oxidative stress and is more susceptible to oxidative stress-induced degeneration in Sorsby Fundus Dystrophy. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4163.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : Sorsby Fundus Dystrophy (SFD) is an autosomal dominant retinal dystrophy that shares a clinical phenotype with Age-related Macular Degeneration (AMD), including the development of sub-retinal deposits, RPE degeneration, and choroidal neovascularization. SFD is caused by mutations in TIMP3 and the Ser179Cys-TIMP3 mutation is associated with severe pathology in patients. We wanted to evaluate if mice carrying the S179C-TIMP3 mutation were more susceptible to oxidative stress-induced RPE degeneration.

Methods : To test oxidative stress, 4-month-old mice (S179C-TIMP3 and age-matched wild-type (WT) littermates) received a single tail vein injection of 10 and 20 mg/kg body weight of NaIO3; parallel groups of mice were injected with PBS. RPE degeneration was evaluated by histology: staining of plastic sections with Toluidene Blue and whole mount immunohistochemistry of RPE/Choroid with phalloidin-TRITC. Quantitative PCR was performed on RPE and retina for antioxidant genes at baseline and under experimental conditions. Reactive oxygen species (ROS) staining was performed on cultured ARPE-19 cells expressing S179C-TIMP3, WT-TIMP3, or vector only control incubated with CM-H2DCFDA, a reagent that is only fluorescent upon oxidation by ROS.

Results : Both WT and S179C-TIMP3 mice developed severe RPE degeneration at 20 mg/kg of NaIO3. However, at the lower dose of NaIO3 (10 mg/kg), only the S179C-TIMP3 mice showed RPE degeneration. DJ-1, Nrf2, Sod1, and Sod2 expression was significantly upregulated in the RPE at baseline S179C-TIMP3 mice compared to WT controls. When S179C-TIMP3 and WT mice were subjected to 10 mg/kg NaIO3, S179C-TIMP3 mice show a trend of downregulation of these same genes while the WT have no change. There was no change in antioxidant gene expression in the retina. Cultured S179C-TIMP3 RPE cells showed increased ROS compared to WT-TIMP3 or vector only cells.

Conclusions : The pathogenic S179C-TIMP3 mutation results in increased ROS in the RPE at baseline, upregulation of antioxidant genes, and increased sucetibility to increased oxidative stress induced by NaIO3. Increased oxidative stress affects mainly the RPE cells in our SFD model.

This is a 2020 ARVO Annual Meeting abstract.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×