title: 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.affiliation: Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
authors.forename: George
authors.initials: G
authors.lastname: Trichonas
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Murakami
authors.forename: Aristomenis
authors.initials: A
authors.lastname: Thanos
authors.forename: Yuki
authors.initials: Y
authors.lastname: Morizane
authors.forename: Maki
authors.initials: M
authors.lastname: Kayama
authors.forename: Christine M
authors.initials: CM
authors.lastname: Debouck
authors.forename: Toshio
authors.initials: T
authors.lastname: Hisatomi
authors.forename: Joan W
authors.initials: JW
authors.lastname: Miller
authors.forename: Demetrios G
authors.initials: DG
authors.lastname: Vavvas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis / Q000473:pathology*; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012163:Retinal Detachment / Q000473:pathology*
chemical_list: D051033:Apoptosis Inducing Factor; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D020690:GTPase-Activating Proteins; C490620:Ralbp1 protein, mouse; D017382:Reactive Oxygen Species; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D020169:Caspases