Autophagy Induction Does Not Protect Retina Against Apoptosis in Ischemia/Reperfusion Model

  • Nathalie Produit-ZengaffinenEmail author
  • Constantin J. Pournaras
  • Daniel F. Schorderet
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 801)


The role played by autophagy after ischemia/reperfusion (I/R) in the retina remains unknown. Our study investigated whether ischemic injury in the retina, which causes an energy crisis, would induce autophagy. Retinal ischemia was induced by elevation of the intraocular pressure and modulation of autophagic markers was analyzed at the protein levels in an early and late phase of recovery. Following retinal ischemia an increase in LC3BII was first observed in the early phase of recovery but did not stay until the late phase of recovery. Post-ischemic induction of autophagy by intravitreal rapamycin administration did not provide protection against the lesion induced by the ischemic stress. On the contrary, an increase in the number of apoptotic cells was observed following I/R in the rapamycin treated retinas.


Retinal ischemia Autophagy Apoptosis LC3 Rapamycin 



Ischemia reperfusion


Microtubule associated protein light chain


Chaperone-mediated autophagy



The authors wish to thank Nicole Gilodi for expert technical help and Sue Houghton for reading the manuscript. This work was supported by a grant from the ProVisu Foundation.


  1. 1.
    Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290(5497):1717–1721PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6(4):463–477PubMedCrossRefGoogle Scholar
  3. 3.
    Buchi ER (1992) Cell death in the rat retina after a pressure-induced ischaemia-reperfusion insult: an electron microscopic study. I. Ganglion cell layer and inner nuclear layer. Exp Eye Res 55(4):605–613PubMedCrossRefGoogle Scholar
  4. 4.
    Kaneda K, Kashii S, Kurosawa T, Kaneko S, Akaike A, Honda Y et al (1999) Apoptotic DNA fragmentation and upregulation of Bax induced by transient ischemia of the rat retina. Brain Res 815(1):11–20PubMedCrossRefGoogle Scholar
  5. 5.
    Zhang Y, Cho CH, Atchaneeyasakul LO, McFarland T, Appukuttan B, Stout JT (2005) Activation of the mitochondrial apoptotic pathway in a rat model of central retinal artery occlusion. Invest Ophthalmol Vis Sci 46(6):2133–2139PubMedCrossRefGoogle Scholar
  6. 6.
    Produit-Zengaffinen N, Pournaras CJ, Schorderet DF (2009) Retinal ischemia-induced apoptosis is associated with alteration in Bax and Bcl-x(L) expression rather than modifications in Bak and Bcl-2. Mol Vis 15:2101–2110PubMedCentralPubMedGoogle Scholar
  7. 7.
    Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22(9):391–397PubMedCrossRefGoogle Scholar
  8. 8.
    Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T et al (2004) The role of autophagy during the early neonatal starvation period. Nature 432(7020):1032–1036PubMedCrossRefGoogle Scholar
  9. 9.
    Shintani T, Klionsky DJ (2004) Autophagy in health and disease: a double-edged sword. Science 306(5698):990–995PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Cuervo AM, Dice JF (2000) Regulation of lamp2a levels in the lysosomal membrane. Traffic 1(7):570–583PubMedCrossRefGoogle Scholar
  11. 11.
    Bandyopadhyay U, Kaushik S, Varticovski L, Cuervo AM (2008) The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane. Mol Cell Biol 28(18):5747–5763PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Hamacher-Brady A, Brady NR, Gottlieb RA (2006) Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. J Biol Chem 281(40):29776–29787PubMedCrossRefGoogle Scholar
  13. 13.
    Qin AP, Zhang HL, Qin ZH (2008) Mechanisms of lysosomal proteases participating in cerebral ischemia-induced neuronal death. Neurosci Bull 24(2):117–123PubMedCrossRefGoogle Scholar
  14. 14.
    Ikeda J, Nakajima T, Osborne OC, Mies G, Nowak TS Jr (1994) Coexpression of c-fos and hsp70 mRNAs in gerbil brain after ischemia: induction threshold, distribution and time course evaluated by in situ hybridization. Brain Res Mol Brain Res 26(1–2):249–258PubMedCrossRefGoogle Scholar
  15. 15.
    Banasiak KJ, Haddad GG (1998) Hypoxia-induced apoptosis: effect of hypoxic severity and role of p53 in neuronal cell death. Brain Res 797(2):295–304PubMedCrossRefGoogle Scholar
  16. 16.
    Esposito C, Grosjean F, Torreggiani M, Esposito V, Mangione F, Villa L et al (2011) Sirolimus prevents short-term renal changes induced by ischemia-reperfusion injury in rats. Am J Nephrol 33(3):239–249PubMedCrossRefGoogle Scholar
  17. 17.
    Yang SS, Liu YB, Yu JB, Fan Y, Tang SY, Duan WT et al (2010) Rapamycin protects heart from ischemia/reperfusion injury independent of autophagy by activating PI3 kinase-Akt pathway and mitochondria K(ATP) channel. Pharmazie 65(10):760–765PubMedGoogle Scholar
  18. 18.
    Liu YB, Yu B, Li SF, Fan Y, Han W, Yu JB et al (2011) Mechanisms mediating the cardioprotective effects of rapamycin in ischaemia-reperfusion injury. Clin Exp Pharmacol Physiol 38(1):77–83PubMedCrossRefGoogle Scholar
  19. 19.
    Piras A, Gianetto D, Conte D, Bosone A, Vercelli A (2011) Activation of autophagy in a rat model of retinal ischemia following high intraocular pressure. PLoS One 6(7):e22514PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Russo R, Berliocchi L, Adornetto A, Varano GP, Cavaliere F, Nucci C et al (2011) Calpain-mediated cleavage of Beclin-1 and autophagy deregulation following retinal ischemic injury in vivo. Cell Death Dis 2:e144PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2014

Authors and Affiliations

  • Nathalie Produit-Zengaffinen
    • 1
    Email author
  • Constantin J. Pournaras
    • 2
  • Daniel F. Schorderet
    • 1
    • 3
    • 4
  1. 1.Institute for Research in OphthalmologySionSwitzerland
  2. 2.Department of NEUCLIDGeneva University HospitalsGenevaSwitzerland
  3. 3.Department of OphthalmologyUniversity of LausanneLausanneSwitzerland
  4. 4.Faculty of Life SciencesEcole polytechnique fédérale de LausanneLausanneSwitzerland

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