Papers

International journal
Dec 14, 2010

Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis.

Proceedings of the National Academy of Sciences of the United States of America
  • George Trichonas
  • ,
  • Yusuke Murakami
  • ,
  • Aristomenis Thanos
  • ,
  • Yuki Morizane
  • ,
  • Maki Kayama
  • ,
  • Christine M Debouck
  • ,
  • Toshio Hisatomi
  • ,
  • Joan W Miller
  • ,
  • Demetrios G Vavvas

Volume
107
Number
50
First page
21695
Last page
700
Language
English
Publishing type
Research paper (scientific journal)
DOI
10.1073/pnas.1009179107

Apoptosis has been shown to be a significant form of cell loss in many diseases. Detachment of photoreceptors from the retinal pigment epithelium, as seen in various retinal disorders, causes photoreceptor loss and subsequent vision decline. Although caspase-dependent apoptotic pathways are activated after retinal detachment, caspase inhibition by the pan-caspase inhibitor Z-VAD fails to prevent photoreceptor death; thus, we investigated other pathways leading to cell loss. Here, we show that receptor interacting protein (RIP) kinase-mediated necrosis is a significant mode of photoreceptor cell loss in an experimental model of retinal detachment and when caspases are inhibited, RIP-mediated necrosis becomes the predominant form of death. RIP3 expression, a key activator of RIP1 kinase, increased more than 10-fold after retinal detachment. Morphological assessment of detached retinas treated with Z-VAD showed decreased apoptosis but significantly increased necrotic photoreceptor death. RIP1 kinase inhibitor necrostatin-1 or Rip3 deficiency substantially prevented those necrotic changes and reduced oxidative stress and mitochondrial release of apoptosis-inducing factor. Thus, RIP kinase-mediated programmed necrosis is a redundant mechanism of photoreceptor death in addition to apoptosis, and simultaneous inhibition of RIP kinases and caspases is essential for effective neuroprotection and may be a novel therapeutic strategy for treatment of retinal disorders.

Link information
DOI
https://doi.org/10.1073/pnas.1009179107
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/21098270
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3003048
ID information
  • DOI : 10.1073/pnas.1009179107
  • Pubmed ID : 21098270
  • Pubmed Central ID : PMC3003048

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