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

Abstract

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.

• Authors: George Trichonas, Yusuke Murakami, Aristomenis Thanos, Yuki Morizane, Maki Kayama, Christine M Debouck, Toshio Hisatomi, Joan W Miller, Demetrios G Vavvas
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 50 Pg. 21695-700 (Dec 14 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 21098270 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Inducing Factor
• Caspase Inhibitors
• Enzyme Inhibitors
• GTPase-Activating Proteins
• Ralbp1 protein, mouse
• Reactive Oxygen Species
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk3 protein, mouse
• Caspases

Topics

• Animals
• Apoptosis (physiology)
• Apoptosis Inducing Factor (metabolism)
• Caspase Inhibitors
• Caspases (metabolism)
• Enzyme Inhibitors (metabolism)
• GTPase-Activating Proteins (genetics, metabolism)
• Mice
• Mice, Knockout
• Necrosis (pathology)
• Photoreceptor Cells, Vertebrate (pathology)
• Rats
• Reactive Oxygen Species (metabolism)
• Receptor-Interacting Protein Serine-Threonine Kinases (genetics, metabolism)
• Retinal Detachment (pathology)