KIT ligand protects against both light-induced and genetic photoreceptor degeneration

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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.

Data availability

Sequencing data have been deposited in GEO under accession codes 146176.All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 1-supplment figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 5-fig supplement 1, Figure 8, Figure 9, Figure 9-supplment figure 1.

The following data sets were generated

1. Li H
2. Hou L
(2020) Next generation sequencing facilitates quantitative analysis of retinal transcriptomes under normal light and high-intensity light condition
NCBI Gene Expression Omnibus, GSE146176.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=gse146176

Article and author information

Author details

Huirong Li

Wenzhou Medical University, Wenzhou, China

Competing interests
The authors declare that no competing interests exist.
Lili Lian

Wenzhou Medical University, Wenzhou, China

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The authors declare that no competing interests exist.
Bo Liu

Wenzhou Medical University, Wenzhou, China

Competing interests
The authors declare that no competing interests exist.
Yu Chen

Wenzhou Medical University, Wenzhou, China

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The authors declare that no competing interests exist.
Jinglei Yang

Wenzhou Medical University, Wenzhou, China

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The authors declare that no competing interests exist.
Shuhui Jian

Wenzhou Medical University, Wenzhou, China

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The authors declare that no competing interests exist.
Jiajia Zhou

Wenzhou Medical University, Wenzhou, China

Competing interests
The authors declare that no competing interests exist.
Ying Xu

GHM Institute of CNS Regeneration, Jinan University, Guangzhou, China

Competing interests
The authors declare that no competing interests exist.
Xiaoyin Ma

Wenzhou Medical University, Wenzhou, China

Competing interests
The authors declare that no competing interests exist.
Jia Qu

Wenzhou Medical University, Wenzhou, China

Competing interests
The authors declare that no competing interests exist.
Ling Hou

Wenzhou Medical University, Wenzhou, China

For correspondence
lhou@eye.ac.cn

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0705-8099

Funding

National Natural Science Foundation of China (81800838)

Huirong Li

National Natural Science Foundation of China (81770946)

Ling Hou

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were carried out in accordance with the approved guidelines of the Wenzhou Medical University Institutional Animal Care and Use Committee (Permit Number: WZMCOPT-090316).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.