AW, a novel HDAC inhibitor, as a potential therapy for early-stage diabetic retinopathy

Abstract

In many developed countries, diabetic retinopathy (DR), one of the complications caused by DM, is a leading cause of vision loss in working-aged adults. AW, a novel histone deacetylase inhibitor (HDACi), was used to investigate the therapeutic potential on DR. Streptozotocin (STZ) was used to induce diabetic condition in C57BL/6 mice, combined with or without hypoxia to mimic DR. We found that STZ combined with hypoxia successfully induced early-stage retinopathy after approximately 2 weeks. Functional assays using electroretinography (ERG) showed abnormal a-wave and b-wave activity. Moreover, morphological observations from fundus photography (FP), fundus fluorescence angiography (FFA) and (OCT) showed yellowish-white spots, hyperfluorescence and reduced thickness of retina. AW dose-dependently prevented diabetes/hypoxia-induced lesions observed from ERG, FP, FFA and OCT. In the part of in vitro study, IL-1β coupled with hypoxia in high-glucose medium was used to simulate DR condition. AW had no changes to the viability of RPE cells and could decrease HIF-1 α protein expression induced by DR condition. The permeability of RPE cells was significantly increased in high glucose/hypoxia/IL-1β condition, and AW could reverse this situation. Western blot revealed that HIF-1α and iNOS were increased, while zona occludens protein 1 (ZO1) and occludin were decreased. To know how AW regulate the expression of HIF-1α,we investigated the related protein. Prolyl hydroxylase domain-containing protein 2 (PHD2) and von Hippel-Lindau protein (vHL) were decreased in hypoxia condition, and recovered by treating with AW. The phosphorylation of mTOR, Akt, p70 was increased by hypoxia, whereas AW could recover this situation, suggested that AW may influence HIF-1α protein expression by the mTOR/Akt/p70 pathway. To sum up, the STZ-combined-hypoxia animal model is suitable for DR study, and AW can lower the worsen of DR, which has a good potential for treating DR.