RT Journal Article
SR Electronic
T1 Light-dependent induction of Edn2 expression and attenuation of retinal pathology by endothelin receptor antagonists in Prominin-1- deficient mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.07.405308
DO 10.1101/2020.12.07.405308
A1 Yuka Kobayashi
A1 Shizuka Watanabe
A1 Manabu Shirai
A1 Chiemi Yamashiro
A1 Tadahiko Ogata
A1 Fumiaki Higashijima
A1 Takuya Yoshimoto
A1 Takahide Hayano
A1 Yoshiyuki Asai
A1 Noriaki Sasai
A1 Kazuhiro Kimura
YR 2020
UL http://biorxiv.org/content/early/2020/12/07/2020.12.07.405308.abstract
AB Retinitis pigmentosa (RP) and macular dystrophy (MD) are prevalent retinal degenerative diseases associated with gradual photoreceptor death. These diseases are often caused by genetic mutations that result in degeneration of the retina postnatally after it has fully developed. The Prominin-1 gene (Prom1) is a causative gene for RP and MD, and Prom1- knockout (KO) mice recapitulate key features of these diseases including light-dependent retinal degeneration and stenosis of retinal blood vessels. The mechanisms underlying progression of such degeneration have remained unknown, however. We here analysed early events associated with retinal degeneration in Prom1-KO mice. We found that photoreceptor cell death and glial cell activation occur between 2 and 3 weeks after birth. High-throughput analysis revealed that expression of the endothelin-2 gene (Edn2) was markedly up-regulated in the Prom1-deficient retina during this period. Expression of Edn2 was also induced by light stimulation in Prom1-KO mice that had been reared in the dark. Finally, treatment with endothelin receptor antagonists attenuated photoreceptor cell death, gliosis, and retinal vessel stenosis in Prom1-KO mice. Our findings suggest that inhibitors of endothelin signalling may delay the progression of RP and MD and therefore warrant further study as potential therapeutic agents for these diseases.Competing Interest StatementThe authors have declared no competing interest.