Abstract
Purpose :
Retinal degenerative diseases cause progressive and irreversible visual impairment while effective therapies are still not available. Hypoxia-inducible factors (HIFs) are transcriptional factors that regulate angiogenesis, erythropoiesis, intracellular metabolism, and programmed cell death mainly depending on oxygen availability. In this study, we investigated the therapeutic effects of halofuginone (HF) focussing on HIFs and its target gene BNIP3 in a murine model of light-induced retinopathy (LIR).
Methods :
The HIF inhibitory effect of HF on CoCl2-induced HIF activity was confirmed by Luciferase assay and qPCR using a 661W cell line. Eight-week-old male BALB/c mice were exposed to white LED light (3000 Lux) for 1 hour to create an LIR model. Neural retinas were harvested from LIR-treated mice, and qPCR and WB were performed to confirm the expression of HIF-1α and BNIP3. Mice were divided into HF group (0.4 mg/kg/day) and PBS group, and HF or PBS was administered 5 times in total before light exposure. Electroretinography (ERG) and Optical Coherence Tomography (OCT) were performed 7 days after light exposure. TUNEL staining was performed on the retinas of LIR model mice treated with HF or PBS.
Results :
Luciferase assay and qPCR using 661W cell line showed that HF significantly suppressed the expression of HIF in a concentration-dependent manner. Light exposure significantly increased the expression of HIF-1α (qPCR: 1.9-fold, p < 0.001; WB: 2.9-fold, p < 0.01) and BNIP3 (qPCR: 1.3-fold, p < 0.05; WB: 1.3-fold, p < 0.05) in the retina. OCT results showed a significant inhibitory effect of HF on the retinal damage. TUNEL staining showed an inhibitory effect of HF on apoptosis of photoreceptors.
Conclusions :
This study suggests the possibility of therapeutic effects of HF on retinal degeneration via the HIF/BNIP3 axis.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.