FGF21 restores photoreceptor function in type 1 diabetic mice

Abstract

Purpose : Diabetic retinopathy (DR) is a common complication in diabetes with vision-threatening neovascularization. Retinal neuronal changes occur before vascular changes in DR. Accumulating experimental evidence suggests that neurons control vascular pathology in neovascular retinal diseases. Therefore, normalizing retinal neuronal activity may prevent vascular pathology. Fibroblast growth factor 21 (FGF21) regulates lipid metabolism in obese patients, non-human primates and mice. We have reported that FGF21 inhibits hypoxia-induced retinal neovascularization in mice, but its impact on retinal neurons is unknown. The purpose of this study is to investigate the impact of FGF21 on retinal function at early DR.

Methods : In diabetic male mice (Akita or streptozotocin-induced), we examined the retinal neuronal activity before and after the long-acting FGF21 analog, PF-05231023 administration by electroretinography (n=5-10), photoreceptor structure with immunohistochemistry (rhodopsin for rods and cone arrestin for cones), as well as retinal thickness by optical coherence tomography (OCT, n=4-10). Retinal and photoreceptor (661W cells) inflammation was examined by Western Blot and qPCR (n=3-4). Correlation of post-receptor cell sensitivity with the sum of changes in photoreceptor in Akita mice was assessed by Pearson r test (n=10). T-test or ANOVA was used for statistical analysis.

Results : In diabetic neural retina, photoreceptor rather than inner retinal function was most affected (post-receptor vs photoreceptor changes: P=0.01). PF-05231023 administration protected against diabetes-induced decrease in retinal sensitivity (Akita vs WT: P=0.00046; PF-05231023- vs vehicle-treated Akita: P=0.00001). PF-05231023 restored disorganization of cone structure seen in retinal cross section and the reduction in the thickness of photoreceptor segments measured by OCT. PF-05231023 reduced pro-inflammatory IL-1β gene expression in diabetic retinas (Akita vs WT: P=0.0483; PF-05231023- vs vehicle-treated Akita: P=0.0036). PF-05231023 activated the AKT pathway and normalized NRF2 levels in diabetic retinas. PF-05231023 administration did not change retinal expression of Vegfa.

Conclusions : Our findings suggest that FGF21 may be a novel therapeutic potential for the prevention of early DR.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.