Light-Dependent Induction of the Inflammatory Pathway and Subsequent Gliosis in Prominin-1-Deficient Mice

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 in which the retina degenerates postnatally after once fully developed. Prominin-1 (Prom1) is one of the causative genes for RP and MD. In previous studies, it has been shown that the Prom1-deficient mice recapitulate the symptoms of the RP and MD; the light dependent retinal degeneration and the stenosis of the retinal blood vessels. However, the mechanisms by which the degeneration progresses remain to be identified. In this study, we analysed the events at the onset of the symptom, and elucidated that the programmed cell death and glial cell proliferation occur during two to three weeks after birth. Next, by means of a high-throughput expression analysis, we identified endothelin-2 (Edn-2) as one of the genes aberrantly upregulated during this step in the Prom1-deficient retina. Moreover, Edn-2 was induced within a three hour-light stimulation, suggesting that Edn-2 is one of the primary responsive genes by light stimuli. Finally we demonstrated that the treatment of endothelin-receptor antagonists, BQ-123 and BQ-788 reduced the programmed cell death and the glial proliferation, as well as the stenosis of the vessels. These findings propose the treatment of the endothelin-inhibitors on the initial stages of RP and MD patients will be an effective therapeutic method to delay the progression of the symptoms.