Endothelin-2-mediated protection of mutant photoreceptors in inherited photoreceptor degeneration

PLoS One. 2013;8(2):e58023. doi: 10.1371/journal.pone.0058023. Epub 2013 Feb 28.

Abstract

Expression of the Endothelin-2 (Edn2) mRNA is greatly increased in the photoreceptors (PRs) of mouse models of inherited PR degeneration (IPD). To examine the role of Edn2 in mutant PR survival, we generated Edn2(-/-) mice carrying homozygous Pde6b(rd1) alleles or the Tg(RHO P347S) transgene. In the Edn2(-/-) background, PR survival increased 110% in Pde6b(rd1/rd1) mice at post-natal (PN) day 15, and 60% in Tg(RHO P347S) mice at PN40. In contrast, PR survival was not increased in retinal explants of Pde6b(rd1/rd1) ; Edn2(-/-) mice. This finding, together with systemic abnormalities in Edn2(-/-) mice, suggested that the increased survival of mutant PRs in the Edn2(-/-) background resulted at least partly from the systemic EDN2 loss of function. To examine directly the role of EDN2 in mutant PRs, we used a scAAV5-Edn2 cDNA vector to restore Edn2 expression in Pde6b(rd1/rd1) ; Edn2(-/-) PRs and observed an 18% increase in PR survival at PN14. Importantly, PR survival was also increased after injection of scAAV5-Edn2 into Pde6b(rd1/rd1) retinas, by 31% at PN15. Together, these findings suggest that increased Edn2 expression is protective to mutant PRs. To begin to elucidate Edn2-mediated mechanisms that contribute to PR survival, we used microarray analysis and identified a cohort of 20 genes with >4-fold increased expression in Tg(RHO P347S) retinas, including Fgf2. Notably, increased expression of the FGF2 protein in Tg(RHO P347S) PRs was ablated in Tg(RHO P347S); Edn2(-/-) retinas. Our findings indicate that the increased expression of PR Edn2 increases PR survival, and suggest that the Edn2-dependent increase in PR expression of FGF2 may contribute to the augmented survival.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Hypoxia / genetics
  • Cell Survival / genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 6 / metabolism
  • Endothelin-2 / genetics
  • Endothelin-2 / metabolism*
  • Fibroblast Growth Factor 2 / metabolism
  • Humans
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Photoreceptor Cells, Vertebrate / metabolism*
  • Photoreceptor Cells, Vertebrate / pathology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Retina / metabolism
  • Retina / pathology
  • Retinal Diseases / genetics*
  • Retinal Diseases / metabolism*
  • Retinal Diseases / pathology
  • Rhodopsin / genetics
  • Signal Transduction / genetics
  • Up-Regulation / genetics

Substances

  • Endothelin-2
  • RNA, Messenger
  • Fibroblast Growth Factor 2
  • Rhodopsin
  • Cyclic Nucleotide Phosphodiesterases, Type 6
  • Pde6b protein, mouse