Induction of necrotic cell death by oxidative stress in retinal pigment epithelial cells

J. Hanus, H. Zhang, Z. Wang, Q. Liu, Q. Zhou, S. Wang

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Age-related macular degeneration (AMD) is a degenerative disease of the retina and the leading cause of blindness in the elderly. Retinal pigment epithelial (RPE) cell death and the resultant photoreceptor apoptosis are characteristic of late-stage dry AMD, especially geographic atrophy (GA). Although oxidative stress and inflammation have been associated with GA, the nature and underlying mechanism for RPE cell death remains controversial, which hinders the development of targeted therapy for dry AMD. The purpose of this study is to systematically dissect the mechanism of RPE cell death induced by oxidative stress. Our results show that characteristic features of apoptosis, including DNA fragmentation, caspase 3 activation, chromatin condensation and apoptotic body formation, were not observed during RPE cell death induced by either hydrogen peroxide or tert-Butyl hydroperoxide. Instead, this kind of cell death can be prevented by RIP kinase inhibitors necrostatins but not caspase inhibitor z-VAD, suggesting necrotic feature of RPE cell death. Moreover, ATP depletion, receptor interacting protein kinase 3 (RIPK3) aggregation, nuclear and plasma membrane leakage and breakdown, which are the cardinal features of necrosis, were observed in RPE cells upon oxidative stress. Silencing of RIPK3, a key protein in necrosis, largely prevented oxidative stressinduced RPE death. The necrotic nature of RPE death is consistent with the release of nuclear protein high mobility group protein B1 into the cytoplasm and cell medium, which induces the expression of inflammatory gene TNFα in healthy RPE and THP-1 cells. Interestingly, features of pyroptosis or autophagy were not observed in oxidative stress-treated RPE cells. Our results unequivocally show that necrosis, but not apoptosis, is a major type of cell death in RPE cells in response to oxidative stress. This suggests that preventing oxidative stress-induced necrotic RPE death may be a viable approach for late-stage dry AMD.

Original languageEnglish (US)
Article numbere965
JournalCell Death and Disease
Volume4
Issue number12
DOIs
StatePublished - Dec 2013

Fingerprint

Retinal Pigments
Oxidative Stress
Cell Death
Epithelial Cells
Macular Degeneration
Geographic Atrophy
Receptor-Interacting Protein Serine-Threonine Kinases
Necrosis
Apoptosis
Protein Kinases
High Mobility Group Proteins
Purinergic P2 Receptors
tert-Butylhydroperoxide
Caspase Inhibitors
Nuclear Envelope
Autophagy
DNA Fragmentation
Blindness
Nuclear Proteins
Caspase 3

Keywords

  • AMD
  • cell death
  • oxidative stress
  • RIPK3
  • RPE cell

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

Induction of necrotic cell death by oxidative stress in retinal pigment epithelial cells. / Hanus, J.; Zhang, H.; Wang, Z.; Liu, Q.; Zhou, Q.; Wang, S.

In: Cell Death and Disease, Vol. 4, No. 12, e965, 12.2013.

Research output: Contribution to journalArticle

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