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Endothelin-2-Mediated Protection of Mutant Photoreceptors in Inherited Photoreceptor Degeneration

Authors
 Alexa N. Bramall  ;  Michael J. Szego  ;  Laura R. Pacione  ;  Inik Chang  ;  Eduardo Diez  ;  Pedro D'Orleans-Juste  ;  Duncan J. Stewart  ;  William W. Hauswirth  ;  Masashi Yanagisawa  ;  Roderick R. McInnes 
Citation
 PLoS One, Vol.8(2) : e58023, 2013 
Journal Title
 PLoS One 
ISSN
 1932-6203 
Issue Date
2013
MeSH
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
Keywords
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
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 Pde6brd1 alleles or the Tg(RHO P347S) transgene. In the Edn2−/− background, PR survival increased 110% in Pde6brd1/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 Pde6brd1/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 Pde6brd1/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 Pde6brd1/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.
Files in This Item:
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DOI
10.1371/journal.pone.0058023
Appears in Collections:
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Chang, In Ik(장인익)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/88574
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