June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Involvement of Autophagy in z-VAD-FMK Induced Photoreceptor Necroptosis, a Caspase-Independent Cell Death, after Experimental Retinal Detachment
Author Affiliations & Notes
  • Kai Dong
    Department of Ophthalmology, Shanghai First People’s Hospital, Shanghai, China
  • Xiaodong Sun
    Department of Ophthalmology, Shanghai First People’s Hospital, Shanghai, China
  • Genjie Ke
    Department of Ophthalmology, the Affiliated Anhui Provincial Hospital of Anhui Medical University, Hefei, Anhui, China, Hefei, China
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 2854. doi:
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      Kai Dong, Xiaodong Sun, Genjie Ke; Involvement of Autophagy in z-VAD-FMK Induced Photoreceptor Necroptosis, a Caspase-Independent Cell Death, after Experimental Retinal Detachment. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2854.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract
 
Purpose
 

Necroptosis is a recently discovered, caspase-independent cell death and necroptosis signaling can accompany autophagy, which may also contribute to neuronal damage. We investigated whether necroptosis induced by z-VAD-FMK was involved the activation of autophagy and whether Necrostatin-1, a specific necroptosis inhibitor, could inhibit this induction of autophagy after experimental retinal detachment.

 
Methods
 

Experimental retinal detachment models were created in Sprague-Dawley rats by subretinal injection of sodium hyaluronate. Subretinal injections of z-VAD-FMK, DMSO or z-VAD-FMK combined with Necrostatin-1 were performed at the time of the retinal detachment induction, respectively.

 
Results
 

Three days after retinal detachment, z-VAD-FMK treatment led to significant reduction of TUNEL-positive photoreceptors but increase of PI-labelled cells compared with DMSO-treated controls. Transmission electron microscope results indicated that z-VAD-FMK induced photoreceptor necroptosis accompanied with extensive vacuolization. Western Blotting further proved LC-3II expression and the activation of autophagy. Western Blotting results showed z-VAD-FMK promotes necroptosis and autophagy by inhibiting caspase-8 activation, promoting RIP1 phosphorylation and LC-3(II) induction. Necrostatin-1 combined with z-VAD-FMK treatment provided significant protection of photoreceptors by simultaneous inhibition of RIP phosphorylation, LC-3(II) induction and caspase activation.

 
Conclusions
 

The results of this study for the first time provided evidence that the activation of autophagy was involved in necroptosis induced by z-VAD-FMK, which could be inhibited by Necrostatin-1 in experimental retinal detachment. These results suggest combination therapy is a potential way to prevent neuronal damage in various retinal disorders associated with photoreceptor loss.

 
 
Triggering members of the death receptor family by death ligands, for example: tumor necrosis factor α, results in the transduction of apoptotic and necroptotic signals. When cells undergo TNF-induced apoptosis, RIP1 phosphorylation is inactivated by caspase-8. Caspase inhibitor, z-VAD-FMK, can switch the death receptor induced apoptotic response to necroptosis by inhibition caspases activation and RIP1 phosphorylation.
 
Triggering members of the death receptor family by death ligands, for example: tumor necrosis factor α, results in the transduction of apoptotic and necroptotic signals. When cells undergo TNF-induced apoptosis, RIP1 phosphorylation is inactivated by caspase-8. Caspase inhibitor, z-VAD-FMK, can switch the death receptor induced apoptotic response to necroptosis by inhibition caspases activation and RIP1 phosphorylation.
 
Keywords: 697 retinal detachment • 426 apoptosis/cell death • 615 neuroprotection  
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