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Abstract
Photoreceptor degeneration is a major cause of blindness and a considerable health burden during aging but effective therapeutic or preventive strategies have not so far become readily available. Here, we show in mouse models that signaling through the tyrosine kinase receptor KIT protects photoreceptor cells against both light-induced and inherited retinal degeneration. Upon light damage, photoreceptor cells upregulate Kit ligand (KITL) and activate KIT signaling, which in turn induces nuclear accumulation of the transcription factor NRF2 and stimulates the expression of the antioxidant gene Hmox1. Conversely, a viable Kit mutation promotes light-induced photoreceptor damage, which is reversed by experimental expression of Hmox1. Furthermore, overexpression of KITL from a viral AAV8 vector prevents photoreceptor cell death and partially restores retinal function after light damage or in genetic models of human retinitis pigmentosa. Hence, application of KITL may provide a novel therapeutic avenue for prevention or treatment of retinal degenerative diseases.
Highlights
Retinal degeneration due to photoreceptor loss is a major threat to human health as progressive vision loss severely interferes with a person’s daily activities
These results suggest that following prolonged light exposure, upregulation of Kit ligand (KITL) leads to activation of KIT signaling
KIT is expressed in mouse retina, including in its photoreceptor cells, and its activation leads to stimulation of the MAPK and the phosphatidylinositol 3’-kinase (PI3K)/AKT pathways
Summary
Retinal degeneration due to photoreceptor loss is a major threat to human health as progressive vision loss severely interferes with a person’s daily activities Such photoreceptor cell loss is common to a number of degenerative eye disorders including cone dystrophy, retinitis pigmentosa (RP) and the highly prevalent age-related macular degeneration (AMD) (Ma et al, 2019; Mitchell et al, 2018; Wright et al, 2010). RP, for instance, has been associated with mutations in about 80 genes and can be inherited as an autosomal-dominant, autosomal-recessive, or X-linked trait (Dias et al, 2018) It is characterized initially by degeneration of rod photoreceptors, followed by a loss of cone photoreceptors and of the photoreceptor-trophic retinal pigment epithelium (RPE). Patients suffer from progressive night blindness, tunnel vision and, rarely, may become totally blind (Dias et al, 2018; Hartong et al, 2006)
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