March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Analysis of the Cellular Stress Response in a Col8a2 Transgenic Knock-in Mouse Model for Fuchs Dystrophy reveals Endothelial Overexpression of Cdkn1a (P21) and Cellular Senescence
Author Affiliations & Notes
  • Mario Matthaei
    The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland
    Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Huan Meng
    The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland
  • Albert S. Jun
    The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland
  • Footnotes
    Commercial Relationships  Mario Matthaei, None; Huan Meng, None; Albert S. Jun, None
  • Footnotes
    Support  Deutsche Forschungsgemeinschaft (DFG MA 5110/2-1 to M.M.), National Institutes of Health (NIH EY019874 to A.S.J.)
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 1739. doi:
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      Mario Matthaei, Huan Meng, Albert S. Jun; Analysis of the Cellular Stress Response in a Col8a2 Transgenic Knock-in Mouse Model for Fuchs Dystrophy reveals Endothelial Overexpression of Cdkn1a (P21) and Cellular Senescence. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1739.

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

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Abstract

Purpose: : Fuchs Endothelial Corneal Dystrophy (FECD) is a common and disabling disease of the corneal endothelium. Large parts of its pathogenesis remain unclear. Stress of the endoplasmic reticulum and oxidative stress have been attributed important pathogenetic roles. In normal corneas, cellular stress is assumed to be at least in part responsible for premature senescence of corneal endothelial cells (CECs) from the corneal center and from older patients in terms of a decrease in proliferative capacity. An endothelial gene expression analysis in our recently developed FECD Col8a2 Q455K transgenic mouse model was performed to further investigate the cellular stress response in FECD.

Methods: : Homozygous Col8a2 Q455K/Q455K mutant (MUT) and wildtype (WT) mice at an age of 12 months were investigated. FECD phenotype was confirmed by clinical confocal microscopy. Descemet membranes and adherent CECs were stripped and RNA was extracted. A PCR array approach was used to analyze differential expression of a panel of 84 cellular stress associated genes.

Results: : Gene array analysis in MUT compared to WT mice showed >2-fold and/or significant (p<0.05) upregulation of 10 genes and downregulation of 13 genes respectively. Result validation by conventional RT-PCR confirmed, inter alia, an overexpression of Cdkn1a/P21 (5.4 fold, p<0.05) also known to be present in senescent cells. RT-PCR analysis of an additional set of senescence associated markers showed statistically significant endothelial upregulation of PAI-1, Sm22, Sparc, Fn1 and Clu. Senescence Associated Beta-Galactosidase Staining of CECs indicated increased numbers of senescent CECs in MUT mice at 5 and 12 months.

Conclusions: : Our data suggests an involvement of stress induced premature senescence (SIPS) in the pathogenesis of FECD. Cdkn1a upregulation and premature senescence may be causally related to the senescence like morphology (cellular flattening and irregularity of shape) of CECs and increased extracellular matrix deposition in FECD.

Keywords: cornea: endothelium 
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