RRC ID 76696
Author Shigesada N, Shikada N, Shirai M, Toriyama M, Higashijima F, Kimura K, Kondo T, Bessho Y, Shinozuka T, Sasai N.
Title Combination of blockade of endothelin signalling and compensation of IGF1 expression protects the retina from degeneration.
Journal Cell Mol Life Sci
Abstract Retinitis pigmentosa (RP) and macular dystrophy (MD) cause severe retinal dysfunction, affecting 1 in 4000 people worldwide. This disease is currently assumed to be intractable, because effective therapeutic methods have not been established, regardless of genetic or sporadic traits. Here, we examined a RP mouse model in which the Prominin-1 (Prom1) gene was deficient and investigated the molecular events occurring at the outset of retinal dysfunction. We extracted the Prom1-deficient retina subjected to light exposure for a short time, conducted single-cell expression profiling, and compared the gene expression with and without stimuli. We identified the cells and genes whose expression levels change directly in response to light stimuli. Among the genes altered by light stimulation, Igf1 was decreased in rod photoreceptor cells and astrocytes under the light-stimulated condition. Consistently, the insulin-like growth factor (IGF) signal was weakened in light-stimulated photoreceptor cells. The recovery of Igf1 expression with the adeno-associated virus (AAV) prevented photoreceptor cell death, and its treatment in combination with the endothelin receptor antagonist led to the blockade of abnormal glial activation and the promotion of glycolysis, thereby resulting in the improvement of retinal functions, as assayed by electroretinography. We additionally demonstrated that the attenuation of mammalian/mechanistic target of rapamycin (mTOR), which mediates IGF signalling, leads to complications in maintaining retinal homeostasis. Together, we propose that combinatorial manipulation of distinct mechanisms is useful for the maintenance of the retinal condition.
Volume 81(1)
Pages 51
Published 2024-1-22
DOI 10.1007/s00018-023-05087-x
PII 10.1007/s00018-023-05087-x
PMID 38252153
PMC PMC10803390
MeSH Animals Endothelins Insulin-Like Growth Factor I / genetics Macular Degeneration* Mice Retina Retinal Diseases* Retinal Rod Photoreceptor Cells Retinitis Pigmentosa*
Mice RBRC05999