Skip to main content

Advertisement

SpringerLink
Log in

Ceramide production associated with retinal apoptosis after retinal detachment

  • Basic Science
  • Published:
Graefe's Archive for Clinical and Experimental Ophthalmology Aims and scope Submit manuscript

Abstract

Background

During retinal detachment, premature apoptosis of photoreceptors and a loss of optimally corrected visual acuity occur. We hypothesized that retinal cell death and generation of ceramide, a pro-apoptotic lipid, would progress as a function of time following experimental retinal detachment, and undertook to define the appropriate temporal window.

Methods

Unilateral retinal detachment was induced in white New Zealand rabbits by subretinal injection of sodium hyaluronate. In experimental animals, we injected sphingosine-1-P into the vitreous 2 hours before retinal detachment. Both eyes were removed on days 1, 3 and 6 for histological and biochemical examination. The number of photoreceptors was counted in section, the level of apoptosis was assessed using the TUNEL assay, and the production of ceramide was analyzed in situ with immunohistochemistry. The concentration of ceramide was also determined on retinal homogenates using a diacylglycerol kinase assay.

Results

We confirmed that the average number of live photoreceptors decreased gradually after retinal detachment. In eyes pre-treated with sphingosine-1-P the number of apoptotic photoreceptors was significantly lower. The proportion of apoptotic photoreceptors (14%) remained constant as a function of time in the window studied. As compared to controls, the detached retina showed intense ceramide immunostaining that was prominent in the photoreceptors, but also present to a lesser extent in other retinal layers. The total concentration of intra-retinal ceramide increased by 40% on the first day and continued augmenting through the sixth day after retinal detachment.

Conclusions

Retinal apoptosis during experimental retinal detachment is associated with in vivo production of ceramide.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Chang CJ, Lai WW, Edward DP, Tso MO (1995) Apoptotic photoreceptor cell death after traumatic retinal detachment in humans. Arch Ophthalmol 113:880–886

    PubMed  CAS  Google Scholar 

  2. Hisatomi T, Sakamoto T, Goto Y, Yamanaka I, Oshima Y, Ishibashi T, Inomata H, Susin SA, Kroemer G (2002) Critical role of photoreceptor apoptosis in functional damage after retinal detachment. Curr Eye Res 24:161–172, doi:10.1076/ceyr.24.3.161.8305

    Article  PubMed  Google Scholar 

  3. Burton TC (1982) Recovery of visual acuity after retinal detachment involving the macula. Trans Am Ophthalmol Soc 80:475–497

    PubMed  CAS  Google Scholar 

  4. Creagh EM, Conroy H, Martin SJ (2003) Caspase-activation pathways in apoptosis and immunity. Immunol 193:10–21, doi:10.1034/j.1600-065X.2003.00048.x

    Article  CAS  Google Scholar 

  5. Cuvillier O, Andrieu-Abadie N, Ségui B, Malagarie-Cazenave S, Tardy C, Bonhoure E, Levade T (2003) Voies de signalisation de l’apoptose médiées par les sphingolipides. J Soc Biol 197:217–221

    PubMed  CAS  Google Scholar 

  6. Levade T, Malagarie-Cazenave S, Gouaze V, Segui B, Tardy C, Betito S, Andrieu-Abadie N, Cuvillier O (2002) Ceramide in apoptosis: a revisited role. Neurochem Res 27:601–607, doi:10.1023/A:1020215815013

    Article  PubMed  CAS  Google Scholar 

  7. Obeid LM, Linardic CM, Karolak LA, Hannun YA (1993) Programmed cell death induced by ceramide. Science 259:1769–1771, doi:10.1126/science.8456305

    Article  PubMed  CAS  Google Scholar 

  8. Hannun YA, Luberto C (2000) Ceramide in the eukaryotic stress response. Trends Cell Biol 10:73–80, doi:10.1016/S0962-8924(99)01694-3

    Article  PubMed  CAS  Google Scholar 

  9. Hla T (2003) Signaling and biological actions of sphingosine 1-phosphate. Pharmacol Res 47(5):401–407, doi:10.1016/S1043-6618(03)00046-X

    Article  PubMed  CAS  Google Scholar 

  10. Olivera A, Rosenfeldt HM, Bektas M, Wang F, Ishii I, Chun J, Milstien S, Spiegel S (2003) Sphingosine kinase type 1 induces G12/13-mediated stress fiber formation, yet promotes growth and survival independent of G protein-coupled receptors. J Biol Chem 278(47):46452–46460, doi:10.1074/jbc.M308749200

    Article  PubMed  CAS  Google Scholar 

  11. Cuvillier O, Pirianov G, Kleuser B, Vanek PG, Coso OA, Gutkind S, Spiegel S (1996) Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 381(6585):800–803, doi:10.1038/381800a0

    Article  PubMed  CAS  Google Scholar 

  12. Lee MJ, Thangada S, Claffey KP, Ancellin N, Liu CH, Kluk M, Volpi M, Sha’afi RI, Hla T (1999) Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell 99(3):301–312, doi:10.1016/S0092-8674(00)81661-X

    Article  PubMed  CAS  Google Scholar 

  13. Morita Y, Perez GI, Paris F, Miranda SR, Ehleiter D, Haimovitz-Friedman A, Fuks Z, Xie Z, Reed JC, Schuchman EH, Kolesnick RN, Tilly JL (2000) Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy. Nat Med 6(10):1109–1114, doi:10.1038/80442

    Article  PubMed  CAS  Google Scholar 

  14. Zelinski MB, Pau F, Murphy M, Lawson M, Fanton J, Tilly J (2006) Intraovarian delivery os sphingosine-1-phosphate protects ovarian follicles from X-irradiation damage in rhesus monkeys. Fertil Steril 86:S95, doi:10.1016/j.fertnstert.2006.07.254

    Article  Google Scholar 

  15. Bonnaud S, Niaudet C, Pottier G, Gaugler MH, Millour J, Barbet J, Sabatier L, Paris F (2007) Sphingosine-1-phosphate protects proliferating endothelial cells from ceramide-induced apoptosis but not from DNA damage-induced mitotic death. Cancer Res 67(4):1803–1811, doi:10.1158/0008-5472.CAN-06-2802

    Article  PubMed  CAS  Google Scholar 

  16. German OL, Miranda GE, Abrahan CE, Rotstein NP (2006) Ceramide is a mediator of apoptosis in retina photoreceptors. Invest Ophthalmol Vis Sci 47:1658–1668, doi:10.1167/iovs.05-1310

    Article  PubMed  Google Scholar 

  17. Sanvicens N, Cotter TG (2006) Ceramide is the key mediator of oxidative stress-induced apoptosis in retinal photoreceptor cells. J Neurochem 98:1432–1444, doi:10.1111/j.1471-4159.2006.03977.x

    Article  PubMed  CAS  Google Scholar 

  18. Berglin L, Algvere PV, Seregard S (1997) Photoreceptor decay over time and apoptosis in experimental retinal detachment. Arch Clin Exp Ophthalmol 235:306–312, doi:10.1007/BF01739640

    Article  CAS  Google Scholar 

  19. Mervin K, Valter K, Maslim J, Lewis G, Fisher S, Stone J (1999) Limiting photoreceptor death and deconstruction during experimental retinal detachment: the value of oxygen supplementation. Am J Ophthalmol 128:155–164, doi:10.1016/S0002-9394(99)00104-X

    Article  PubMed  CAS  Google Scholar 

  20. Francke E, Faude F, Pannicke T, Bringmann A, Eckstein P, Reichelt W, Wiedemann P, Reichenbach A (2001) Electrophysiology of rabbit Muller (glial) cells in experimental retinal detachment and PVR. Invest Ophthalmol Vis Sci 45:1072–1079

    Google Scholar 

  21. Zacks DN, Hanninen V, Pantcheva M, Ezra E, Grosskreutz C, Miller JW (2003) Caspase activation in an experimental model of retinal detachment. Invest Ophthalmol Vis Sci 44:1262–1267, doi:10.1167/iovs.02-0492

    Article  PubMed  Google Scholar 

  22. Bielawska A, Perry DK, Hannun YA (2001) Determination of ceramides and diglycerides by the diglyceride kinase assay. Anal Biochem 298:141–150, doi:10.1006/abio.2001.5342

    Article  PubMed  CAS  Google Scholar 

  23. Ames B (1966) Assay of inorganic phosphate, total phosphate and phosphatases. Methods Enzymol 8:115–118, doi:10.1016/0076-6879(66)08014-5

    Article  CAS  Google Scholar 

  24. Kawase M, Watanabe M, Kondo T, Yabu T, Taguchi Y, Umehara H, Uchiyama T, Mizuno K, Okazaki T (2002) Increase of ceramide in adriamycin-induced HL-60 cell apoptosis: detection by a novel anti-ceramide antibody. Biochim Biophys Acta 1584(2–3):104–114

    PubMed  CAS  Google Scholar 

  25. Medin JA, Takenaka T, Carpentier S (1999) Retrovirus-mediated correction of the metabolic defect in cultured Farber disease cells. Hum Gene Ther 10:1321–1329, doi:10.1089/10430349950018003

    Article  PubMed  CAS  Google Scholar 

  26. Cook B, Lewis GP, Fisher SK, Adler R (1995) Apoptotic photoreceptor degeneration in experimental retinal detachment. Invest Ophthalmol Vis Sci 36:990–996

    PubMed  CAS  Google Scholar 

  27. Abler AS, Chang CJ, Ful J, Tso MO, Lam TT (1996) Photic injury triggers apoptosis of photoreceptor cells. Res Commun Mol Pathol Pharmacol 92:177–189

    PubMed  CAS  Google Scholar 

  28. Shahinfar S, Edward DP, Tso MO (1991) A pathologic study of photoreceptor cell death in retinal photic injury. Curr Eye Res 10:47–59, doi:10.3109/02713689109007610

    Article  PubMed  CAS  Google Scholar 

  29. Tso MO, Zhang C, Abler AS, Chang CJ, Wong F, Chang GQ, Lam TT (1994) Apoptosis leads to photoreceptor degeneration in inherited retinal dystrophy of RCS rats. Invest Ophthalmol Vis Sci 35:2693–2699

    PubMed  CAS  Google Scholar 

  30. Hafezi F, Steinbach JP, Marti A, Munz K, Wang ZQ, Wagner EF, Aguzzi A, Reme CE (1997) The absence of c-fos prevents light-induced apoptotic cell death of photoreceptors in retinal degeneration in vivo. Nat Med 3:346–349, doi:10.1038/nm0397-346

    Article  PubMed  CAS  Google Scholar 

  31. Portera-Cailliau C, Sung CH, Nathans J, Adler R (1994) Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa. Proc Natl Acad Sci USA 91:974–978, doi:10.1073/pnas.91.3.974

    Article  PubMed  CAS  Google Scholar 

  32. Anderson DH, Guerin CJ, Erickson PA, Stern WH, Fisher SK (1986) Morphological recovery in the reattached retina. Invest Ophthalmol Vis Sci 27:168–183

    PubMed  CAS  Google Scholar 

  33. Guerin CJ, Lewis GP, Fisher SK, Anderson DH (1993) Recovery of photoreceptor outer segment length and analysis of membrane assembly rates in regenerating primate photoreceptor outer segments. Invest Ophthalmol Vis Sci 34:175–183

    PubMed  CAS  Google Scholar 

  34. Arroyo JG, Yanf L, Bula D, Chen DF (2005) Photoreceptor apoptosis in human retinal detachment. Am J Ophthalmol 139:05–610

    Article  Google Scholar 

  35. Zarbin MA, Green WR, Moser AB, Tiffany C (1988) Increased levels of ceramide in the retina of a patient with Farber’s disease. Arch Ophthalmol 106:1163

    PubMed  CAS  Google Scholar 

  36. Watanabe M, Kitano T, Kondo T, Yabu T, Taguchi Y, Tashima M, Umehara H, Domae N, Uchiyama T, Okazaki T (2004) Increase of nuclear ceramide through caspase-3-dependent regulation of the “sphingomyelin cycle” in Fas-induced apoptosis. Cancer Res 64:1000–1007, doi:10.1158/0008-5472.CAN-03-1383

    Article  PubMed  CAS  Google Scholar 

  37. Tsugane K, Tamiya-Koizumi K, Nagino M, Nimura Y, Yoshida SA (1999) Possible role of nuclear ceramide and sphingosine in hepatocyte apoptosis in rat liver. J Hepatol 31:8–17, doi:10.1016/S0168-8278(99)80158-5

    Article  PubMed  CAS  Google Scholar 

  38. Vielhaber G, Pfeiffer S, Brade L, Lindner B, Goldmann T, Vollmer E, Hintze U, Wittern KP, Wepf R (2001) Localization of Ceramide and glucosylceramide in human epidermis by immunogold electron microscopy. J Invest Dermatol 117:1126–1136, doi:10.1046/j.0022-202x.2001.01527.x

    Article  PubMed  CAS  Google Scholar 

  39. Levade T, Jaffrezou JP (1999) Signalling sphingomyelinases: which, where, how and why? Biochim Biophys Acta 1438:1–17

    PubMed  CAS  Google Scholar 

  40. Barak A, Morse LS, Goldkorn T (2001) Ceramide: a potential mediator of apoptosis in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 42:247–254

    PubMed  CAS  Google Scholar 

  41. Mathias S, Pena LA, Kolesnick RN (1998) Signal transduction of stress via ceramide. Biochem J 335:465–480

    PubMed  CAS  Google Scholar 

  42. Barak A, Goldkorn T, Morse LS (2005) Laser induces apoptosis and ceramide production in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 46:2587–2591, doi:10.1167/iovs.04-0920

    Article  PubMed  Google Scholar 

  43. Cuvillier O, Rosenthal DS, Smulson ME, Spiegel S (1998) Sphingosine 1-phosphate inhibits activation of caspases that cleave poly(ADP-ribose) polymerase and lamins during Fas- and ceramide-mediated apoptosis in Jurkat T lymphocytes. J Biol Chem 273(5):2910–2916

    Article  PubMed  CAS  Google Scholar 

  44. Edsall LC, Cuvillier O, Twitty S, Spiegel S, Milstien S (2001) Sphingosine kinase expression regulates apoptosis and caspase activation in PC12 cells. J Neurochem 76(5):1573–1584, doi:10.1046/j.1471-4159.2001.00164.x

    Article  PubMed  CAS  Google Scholar 

  45. Spiegel S, Cuvillier O, Edsall LC, Kohama T, Menzeleev R, Olah Z, Olivera A, Pirianov G, Thomas DM, Tu Z, Van Brocklyn JR, Wang F (1998) Sphingosine-1-phosphate in cell growth and cell death. Ann N Y Acad Sci 845:11–18, doi:10.1111/j.1749-6632.1998.tb09658.x

    Article  PubMed  CAS  Google Scholar 

  46. Kester M, Kolesnick R (2003) Sphingolipids as therapeutics. Pharmacol Res 47(5):365–371, doi:10.1016/S1043-6618(03)00048-3

    Article  PubMed  CAS  Google Scholar 

  47. Hancke K, Strauch O, Kissel C, Gobel H, Schafer W, Denschlag D (2007) Sphingosine 1-phosphate protects ovaries from chemotherapy-induced damage in vivo. Fertil Steril 87(1):172–177, doi:10.1016/j.fertnstert.2006.06.020

    Article  PubMed  CAS  Google Scholar 

  48. Otala M, Suomalainen L, Pentikainen MO, Kovanen P, Tenhunen M, Erkkila K, Toppari J, Dunkel L (2004) Protection from radiation-induced male germ cell loss by sphingosine-1-phosphate. Biol Reprod 70(3):759–767, doi:10.1095/biolreprod.103.021840

    Article  PubMed  CAS  Google Scholar 

  49. Nakazawa T, Hisatomi T, Nakazawa C, Noda K, Maruyama K, She H, Matsubara A, Miyahara S, Nakao S, Yin Y, Benowitz L, Hafezi-Moghadam A, Miller JW (2007) Monocyte chemoattractant protein 1 mediates retinal detachment-induced photoreceptor apoptosis. Proc Natl Acad Sci USA 104(7):2425–2430

    Article  PubMed  CAS  Google Scholar 

  50. Lewis GP, Linberg KA, Geller SF, Guérin CJ, Fisher SK (1999) Effects of the neurotrophin brain-derived neurotrophic factor in an experimental model of retinal detachment. Invest Ophthalmol Vis Sci 40(7):1530–1544

    PubMed  CAS  Google Scholar 

  51. Chong DY, Boehlke CS, Zheng QD, Zhang L, Han Y, Zacks DN (2008) Interleukin-6 as a photoreceptor neuroprotectant in an experimental model of retinal detachment. Invest Ophthalmol Vis Sci 49(7):3193–3200, doi:10.1167/iovs.07-1641

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. T. Okazaki (Kyoto, Japan) for providing the anti-ceramide antibody against ceramide, L. Larrié and M. Mathieu for technical assistance, and Dr. H. Etchevers for constructive comments.

Author information

Authors and Affiliations

  1. Service d’Anatomie Pathologique, CHU Rangueil, Toulouse, 31000, France

    Marie-Laure Ranty & Marie-Bernadette Delisle

  2. Inserm, U858, Institut de Médecine Moléculaire de Rangueil, Toulouse, 31432, France

    Stéphane Carpentier, Thierry Levade & Marie-Bernadette Delisle

  3. Université Toulouse III Paul Sabatier, Toulouse, 31000, France

    Stéphane Carpentier, Isabelle Rico-Lattes, François Malecaze, Thierry Levade, Marie-Bernadette Delisle & Jean-Claude Quintyn

  4. Service d’Epidémiologie, Hôtel Dieu, Toulouse, 31000, France

    Maxime Cournot

  5. Laboratoire des IMRCP, UMR CNRS 5623, Toulouse, 31000, France

    Isabelle Rico-Lattes & Jean-Claude Quintyn

  6. Inserm, U563, CHU Purpan, Toulouse, 31300, France

    François Malecaze & Jean-Claude Quintyn

  7. Service d’Ophtalmologie, CHU Purpan, 31300, Toulouse, France

    François Malecaze

  8. Service d’Ophtalmologie, CHU Rangueil, 31000, Toulouse, France

    Jean-Claude Quintyn

  9. Service d’Ophtalmologie, CHU Rangueil—TSA 50032, 31059, Toulouse Cedex 9, France

    Jean-Claude Quintyn

Authors
  1. Marie-Laure Ranty
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stéphane Carpentier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maxime Cournot
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Isabelle Rico-Lattes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. François Malecaze
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thierry Levade
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marie-Bernadette Delisle
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jean-Claude Quintyn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jean-Claude Quintyn.

Additional information

There is no financial relationship with an organisation.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ranty, ML., Carpentier, S., Cournot, M. et al. Ceramide production associated with retinal apoptosis after retinal detachment. Graefes Arch Clin Exp Ophthalmol 247, 215–224 (2009). https://doi.org/10.1007/s00417-008-0957-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00417-008-0957-6

Keywords

Search

Navigation