Combination of blockade of endothelin signalling and compensation of IGF1 expression confers protective effects on degenerating retina

Abstract

Abstract Retinitis pigmentosa (RP) and macular dystrophy (MD) cause severe retinal dysfunction, from which 1 in 4,000 people suffer 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 took advantage of RP model mice in which the Prominin-1 (Prom1) gene is 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, carried out single-cell expression profiling, and compared the gene expression with that 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, we found that Igf1 was decreased in rod photoreceptor cells and astrocytes under light-stimulated conditions. Consistently, the insulin-like growth factor (IGF) signal was weakened in the light-stimulated photoreceptor cells. The recovery of Igf1expression 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, and thereby resulted 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 retinal homeostasis. Together, we propose that combinatorial manipulation of distinct mechanisms is useful for the maintenance of the retinal condition.