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

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