Skip to main content

Advertisement

SpringerLink
Log in

Possible implications of acid-sensing ion channels in ischemia-induced retinal injury in rats

  • Laboratory Investigation
  • Published:
Japanese Journal of Ophthalmology Aims and scope Submit manuscript

Abstract

Background

Retinal ischemia in eyes with diabetic retinopathy and retinal vein occlusion leads to local tissue acidosis. Acid-sensing ion channels (ASICs) are expressed in photoreceptors and other neurons in the retina, and may play a role in acid-induced cell injury. The purpose of this study was to investigate the neuroprotective effects of amiloride, an ASIC blocker, on induced retinal ischemia in rats.

Methods

Transient retinal ischemia was induced in male Long–Evans rats by the temporary ligation of the optic nerve. Just before the induction of ischemia, the experimental eyes underwent intravitreal injection of amiloride. On day 7, the retinal damage in eyes that underwent amiloride treatment (and in those that did not undergo the treatment) was evaluated by histology and electroretinogram (ERG).

Results

Transient retinal ischemia caused retinal degeneration with thinning of the inner layer of the retina. The blockage of ASICs with amiloride significantly prevented retinal degeneration. ERG demonstrated that the reduction in a- and b-wave amplitudes induced by the transient retinal ischemia was significantly prevented by the application of amiloride.

Conclusions

The present study suggests that ASICs might, at least in part, play a pathophysiological role in ischemia-induced neurodegeneration. Blockage of ASICs may have a potential neuroprotective effect in ocular ischemic diseases.

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

Similar content being viewed by others

References

  1. Osborne NN, Casson RJ, Wood JP, Chidlow G, Graham M, Melena J. Retinal ischemia: mechanisms of damage and potential therapeutic strategies. Prog Retin Eye Res. 2004;93:91–147.

    Article  Google Scholar 

  2. Tsujikawa A, Ogura Y, Hiroshiba N, Miyamoto K, Kiryu J, Honda Y. In vivo evaluation of leukocyte dynamics in retinal ischemia reperfusion injury. Invest Ophthalmol Vis Sci. 1998;39:793–800.

    PubMed  CAS  Google Scholar 

  3. Nicholls D, Attell D. The release and uptake of excitatory amino acids. Trends Pharmacol Sci. 1990;11:462–7.

    Article  PubMed  Google Scholar 

  4. Choi DW. Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci. 1988;11:465–9.

    Article  PubMed  CAS  Google Scholar 

  5. Rothman SM, Olney JW. Excitotoxicity and the NMDA receptor—still lethal after eight years. Trends Neurosci. 1995;18:57–8.

    Article  PubMed  CAS  Google Scholar 

  6. Mori H, Mishina M. Structure and function of the NMDA receptor channel. Neuropharmacology. 1995;34:1219–37.

    Article  PubMed  CAS  Google Scholar 

  7. Sucher NJ, Lipton SA, Dreyer EB. Molecular basis of glutamate toxicity in retinal ganglion cells. Vis Res. 1997;37:3483–93.

    Article  PubMed  CAS  Google Scholar 

  8. Tymianski C. Cytosolic calcium concentrations and cell death in vitro. Adv Neurol. 1996;71:85–105.

    PubMed  CAS  Google Scholar 

  9. Lee JM, Zipfel GJ, Choi DW. The changing landscape of ischaemic brain injury mechanisms. Nature. 1999;399:A7–14.

    Article  PubMed  CAS  Google Scholar 

  10. Wahlgren NG, Ahmed N. Neuroprotection in cerebral ischaemia: facts and fancies—the need for new approaches. Cerebrovasc Dis. 2004;17:153–66.

    Google Scholar 

  11. Lombardi G, Moroni F, Moroni F. Glutamate receptor antagonists protect against ischemia-induced retinal damage. Eur J Pharmacol. 1994;271:489–95.

    Article  PubMed  CAS  Google Scholar 

  12. Rehncrona S. Brain acidosis. Ann Emerg Med. 1985;14:770–6.

    Article  PubMed  CAS  Google Scholar 

  13. Waldmann R, Champigny G, Bassilana F, Heurteaux C, Lazdunski M. A proton-gated cation channel involved in acid-sensing. Nature. 1997;386:173–7.

    Article  PubMed  CAS  Google Scholar 

  14. Krishtal O. The ASICs: signaling molecules? Modulators? Trends Neurosci. 2003;26:477–83.

    Article  PubMed  CAS  Google Scholar 

  15. Ugawa S, Ueda T, Ishida Y, Nishigaki M, Shibata Y, Shimada S. Amiloride-blockable acid sensing ion channels are leading acid sensors expressed in human nociceptors. J Clin Invest. 2002;110:1185–90.

    PubMed  CAS  Google Scholar 

  16. Kellenberger S, Schild L. Epithelial sodium channel/degenerin family of ion channels: a variety of function for a shared structure. Physiol Rev. 2002;82:735–67.

    PubMed  CAS  Google Scholar 

  17. Champigny G, Voilley N, Waldmann R, Lazdunski M. Mutations causing neurodegeneration in Caenorhabditis elegans drastically alter the pH sensitivity and inactivation of the mammalian H+-gated Na+ channel MDEG1. J Biol Chem. 1998;25:15418–22.

    Article  Google Scholar 

  18. Xiong ZG, Chu XP, Simon RP. Ca2+-permeable ion channels and ischemic brain injury. J Membr Biol. 2006;209:59–68.

    Article  PubMed  CAS  Google Scholar 

  19. Xiong ZG, Zhu XM, Chu XP, Minami M, Hey J, Wei WL, et al. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell. 2004;118:687–98.

    Article  PubMed  CAS  Google Scholar 

  20. Hu W, Chen FH, Yuan FL, Zhang TY, Wu FR, Rong C, et al. Blockade of acid-sensing ion channels protects articular chondrocytes from acid-induced apoptotic injury. Inflamm Res. 2012;61:327–35.

    Article  PubMed  CAS  Google Scholar 

  21. Duan B, Wang YZ, Yang T, Chu XP, Yu Y, Huang Y, et al. Extracellular spermine exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. J Neurosci. 2011;31:2101–12.

    Article  PubMed  CAS  Google Scholar 

  22. Brockway LM, Zhou ZH, Bubien JK, Jovov B, Benos DJ, Keyser KT. Rabbit retinal neurons and glia express a variety of EnaC/DEG subunits. Am J Physiol Cell Physiol. 2002;283:C126–34.

    PubMed  CAS  Google Scholar 

  23. Lilley S, LeTissier P, Robbins J. The discovery and characterization of a proton-gated sodium current in rat retinal ganglion cells. J Neurosci. 2004;24:1013–22.

    Article  PubMed  CAS  Google Scholar 

  24. Ettaiche M, Deval E, Cougnon M, Lazdunski M, Voilley N. Silencing acid-sensing ion channel 1a alters cone-mediated retinal function. J Neurosci. 2006;26:5800–9.

    Article  PubMed  CAS  Google Scholar 

  25. Ettaiche M, Guy N, Hofman P, Lazdunski M, Waldmann R. Acid-sensing ion channel 2 is important for retinal function and protects against light-induced retinal degeneration. J Neurosci. 2004;24:1005–12.

    Article  PubMed  CAS  Google Scholar 

  26. Mizuno S, Nishiwaki A, Morita H, Miyake T, Ogura Y. Effect of periocular administration of triamcinolone acetonide on leukocyte-endothelium interactions in the ischemic retina. Invest Ophthalmol Vis Sci. 2007;48:2831–6.

    Article  PubMed  Google Scholar 

  27. Berkowitz BA, Lukaszew RA, Mullins CM, Penn JS. Impaired hyaloidal circulation function and uncoordinated ocular growth patters in experimental retinopathy of prematurity. Invest Ophthalmol Vis Sci. 1998;39:391–6.

    PubMed  CAS  Google Scholar 

  28. Hughes WF. Quantitation of ischemic damage in the rat retina. Exp Eye Res. 1991;53:573–82.

    Article  PubMed  CAS  Google Scholar 

  29. Machida S, Kondo M, Jamison JA, Khan NW, Kononen LT, Sugawara T, et al. P23H rhodopsin transgenic rat: correlation of retinal function with histopathology. Invest Ophthalmol Vis Sci. 2000;41:3200–9.

    PubMed  CAS  Google Scholar 

  30. Ettaiche M, Deval E, Pagnotta S, Lazdunski M, Lingueglia E. Acid-sensing ion channel 3 in retinal function and survival. Invest Ophthalmol Vis Sci. 2009;50:2417–26.

    Article  PubMed  Google Scholar 

  31. Tan J, Ye X, Xu Y, Wang H, Sheng M, Wang F. Acid-sensing ion channel 1a is involved in retinal ganglion cell death induced by hypoxia. Mol Vis. 2011;17:3300–8.

    PubMed  CAS  Google Scholar 

  32. Brockway LM, Benos DJ, Keyser KT, Kraft TW. Blockade of amiloride-sensitive sodium channels alters multiple components of the mammalian electroretinogram. Vis Neurosci. 2005;22:143–51.

    Article  PubMed  Google Scholar 

  33. Gao J, Duan B, Wang DG, Deng XH, Zhang GY, Xu L, et al. Coupling between NMDA receptor and acid-sensing ion channel contributes to ischemic neuronal death. Neuron. 2005;48:635–46.

    Article  PubMed  CAS  Google Scholar 

  34. Nakazawa T, Watanabe M, Kudo H, Nishida K, Tamai M. Susceptibility to N-methyl-d-aspartate toxicity in morphological and functional types of cat retinal ganglion cells. Jpn J Ophthalmol. 2010;54:156–62.

    Article  PubMed  CAS  Google Scholar 

  35. Tan J, Ye X, Xu Y, Wang H, Sheng M, Wang F. Acid-sensing ion channel 1a is involved in retinal ganglion cell death induced by hypoxia. Mol Vis. 2011;17:3300–8.

    PubMed  CAS  Google Scholar 

  36. Ogishima H, Nakamura S, Nakanishi T, Imai S, Kakino M, Ishizuka F, et al. Ligation of the pterygopalatine and external carotid arteries induces ischemic damage in the murine retina. Invest Ophthalmol Vis Sci. 2011;52:9710–20.

    Article  PubMed  Google Scholar 

  37. Mizote M, Hirooka K, Fukuda K, Nakamura T, Itano T, Shiraga F. d-allose as ischemic retina injury inhibitor during rabbit vitrectomy. Jpn J Ophthalmol. 2011;55:294–300.

    Article  PubMed  CAS  Google Scholar 

  38. Tang CM, Presser F, Morad M. Amiloride selectively blocks the low threshold (T) calcium channel. Science. 1988;240:213–5.

    Article  PubMed  CAS  Google Scholar 

  39. Palandoken H, By K, Hegde M, Harley WR, Gorin FA, Nantz MH. Amiloride peptide conjugates: prodrugs for sodium-proton exchange inhibition. J Pharmacol Exp Ther. 2005;312:961–7.

    Article  PubMed  CAS  Google Scholar 

  40. Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisber JD, et al. Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. Nature. 1994;367:463–7.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We wish to thank K. Miyata and M. Kondo for their technical assistance in measuring the ERG.

Conflict of interest

The authors declare that they have no competing financial interests.

Author information

Authors and Affiliations

  1. Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan

    Takatomo Miyake, Akiko Nishiwaki, Tsutomu Yasukawa & Yuichiro Ogura

  2. Department of Neuronal Cell Biology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Shoichi Shimada

  3. Department of Anatomy and Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan

    Shinya Ugawa

Authors
  1. Takatomo Miyake
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akiko Nishiwaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tsutomu Yasukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shinya Ugawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shoichi Shimada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuichiro Ogura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akiko Nishiwaki.

About this article

Cite this article

Miyake, T., Nishiwaki, A., Yasukawa, T. et al. Possible implications of acid-sensing ion channels in ischemia-induced retinal injury in rats. Jpn J Ophthalmol 57, 120–125 (2013). https://doi.org/10.1007/s10384-012-0213-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10384-012-0213-9

Keywords

Search

Navigation