Purchase this article with an account.
Y. Murakami, G. Trichonas, A. Thanos, Y. Morizane, S. Jardeleza, T. Hisatomi, E. S. Gragoudas, J. W. Miller, D. Vavvas; Receptor Interacting Protein 1 Kinase is an Essential Mediator of Programmed Photoreceptor Necrosis After Retinal Detachment. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4034.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
To investigate the role of receptor interacting protein 1 (RIP1) kinase during photoreceptor death after retinal detachment (RD).
RD was created in the eyes of Brown Norway rats by subretinal injection of viscoelastic (Provisc). The eyes without RD were used as a control. Expression levels of RIP family members were assessed by quantitative real-time PCR. Treated eyes received Z-VAD (pan-caspase inhibitor) and/or necrostatin-1 (RIP1 kinase inhibitor) injected subretinally at the time of RD induction. Photoreceptor death was evaluated by transmission electron microscopy and changes of outer nuclear layer thickness at 3 days after RD. Oxidative stress in the retina was assessed by ELISA for carbonyl adducts on proteins. Cellular localization of apoptosis-inducing factor (AIF) was assessed by immunostaining.
RIP3 expression, a key activator of RIP1 kinase, increased over 10-fold in the retina 3 days after RD. Caspase inhibition by Z-VAD failed to prevent photoreceptor loss after RD; however, ultrastructural analysis revealed that the form of photoreceptor death changed from apoptosis to necrosis. These necrotic changes observed in Z-VAD-treated retina were substantially prevented by combined treatment with necrostatin-1 and Z-VAD, along with a reduction in oxidative stress and the nuclear translocation of AIF.
These findings indicate that RIP1 kinase plays an essential role after RD to induce programmed necrosis and that simultaneous inhibition of RIP1 kinase and caspases may be a novel therapeutic strategy to prevent photoreceptor death after RD.
This PDF is available to Subscribers Only