April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Decline in DJ-1 in Fuchs Endothelial Corneal Dystrophy
Author Affiliations & Notes
  • Ula V. Jurkunas
    Dept of Ophthalmology/Harvard Med Sch, Mass Eye&Ear Infirmary; Schepens Eye Res, Boston, Massachusetts
  • Maya Bitar
    Dept of Ophthalmology/Harvard Med Sch, Schepens Eye Research, Boston, Massachusetts
  • Yuming Chen
    Dept of Ophthalmology/Harvard Med Sch, Schepens Eye Research, Boston, Massachusetts
  • Behrooz Azizi
    Dept of Ophthalmology/Harvard Med Sch, Schepens Eye Research, Boston, Massachusetts
  • Footnotes
    Commercial Relationships  Ula V. Jurkunas, None; Maya Bitar, None; Yuming Chen, None; Behrooz Azizi, None
  • Footnotes
    Support  R01 EY020581
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 6469. doi:
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    • Get Citation

      Ula V. Jurkunas, Maya Bitar, Yuming Chen, Behrooz Azizi; Decline in DJ-1 in Fuchs Endothelial Corneal Dystrophy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6469.

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

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Abstract
 
Purpose:
 

Oxidative stress is a contributor to Fuchs corneal endothelial dystrophy (FECD) pathogenesis. We detected decreased expression of antioxidant enzymes known to be regulated by nuclear factor erythroid 2-related factor 2 (Nrf2) in FECD. The purpose of this study was to determine the role of Nrf2 transcription factor and its regulators in corneal endothelial cell (CEC) susceptibility to oxidative stress seen in FECD.

 
Methods:
 

Human corneal endothelial cell-Descemet’s membrane (HCEC-DM) complexes were dissected from the stroma of normal and FECD specimens. CECs were treated with tBHP (0, 500, 1000 µM) for 4 h at room temperature. Real-time PCR and western blotting were used to detect levels of Nrf1, Nrf2, Keap1, and DJ-1. Cellular apoptosis and oxidative DNA damage were assessed by TUNEL assay and immunocytochemical analysis using anti-8OHdG antibody, respectively.

 
Results:
 

Significant decrease in Nrf2 protein levels (n=12, p=0.03) with no change in Nrf2 mRNA expression was detected in FECD samples as compared to normal controls. Similarly, levels of Nrf1 and Keap 1 (a protein that targets Nrf2 for proteosomal degradation) mRNA levels were unchanged. Two-fold decrease in DJ-1 (a protein that stabilizes Nrf2 protein by impairing proteosomal degradation) level (p=0.04) was accompanied by significant decrease in DJ-1 mRNA expression (n=12, p=0.02) in FECD as compared to normal CECs. Pro-oxidant treatments increased apoptotic rate and oxidative DNA damage in FECD CEC; in response to tBHP exposure, DJ-1 production was 6-fold higher (p=0.003) in normal CEC as compared to FECD CEC while Keap1 protein synthesis increased by 4-fold in FECD as compared to normal CECs (p=0.03).

 
Conclusions:
 

Decreased Nrf2 protein stability in FECD could be related to decrease in expression of its stabilizer, DJ-1 protein. Elevated Keap 1 levels in FECD potentially signify heightened Nrf2 proteosomal degradation. Susceptibility of FECD-affected corneal endothelium to oxidative stress is likely related to diminished Nrf2-regulated antioxidant defense.  

 
Keywords: cornea: endothelium • oxidation/oxidative or free radical damage • transcription factors 
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