Prematurely senescent ARPE-19 cells display features of age-related macular degeneration

Anne Lise Glotin, Florence Debacq-Chainiaux, Jean Yves Brossas, Anne Marie Faussat, Jacques Tréton, Anna Zubielewicz, Olivier Toussaint, Frédéric Mascarelli

Research output: Contribution to journalArticlepeer-review

Abstract

The etiology of age-related macular degeneration (AMD), the leading cause of blindness in the developed world, remains poorly understood, but may be related to cumulative oxidative stress. The prime target of the disease is the retinal pigmented epithelium (RPE). To study the molecular mechanisms underlying RPE degeneration, we investigated whether repetitive oxidative stress induced premature senescence in RPE cells from the human ARPE-19 cell line. After exposure to 8 mM tert-butylhydroperoxide (tert-BHP) for 1 h daily for 5 days, the cells showed four well-known senescence biomarkers: hypertrophy, senescence-associated β-galactosidase activity, growth arrest, and cell cycle arrest in G1. A specific low-density array followed by qRT-PCR validation allowed us to identify 36 senescence-associated genes differentially expressed in the prematurely senescent cells. Functional analysis demonstrated that premature senescence induced amyloid β secretion, resistance to acute stress by tert-BHP and amyloid β, and defects in adhesion and transepithelial permeability. Coculture assays with choroidal endothelial cells showed the proangiogenic properties of the senescent RPE cells. These results demonstrate that chronic oxidative stress induces premature senescence in RPE cells that modifies the transcriptome and substantially alters cell processes involved in the pathophysiology of AMD. Oxidative stress-induced premature senescence may represent an in vitro model for screening therapeutics against AMD and other retinal degeneration disorders. © 2007 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)1348-1361
Number of pages14
JournalFree Radical Biology and Medicine
Volume44
Issue number7
DOIs
Publication statusPublished - 1 Apr 2008

Keywords

  • Aging
  • Amyloid β
  • Angiogenesis
  • Free radicals
  • Retina
  • Tight junction
  • Transcriptome

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