Effects of clinically available HIF-PH inhibitors on retinal Vegfa transcription

Abstract Hypoxia-inducible factor (HIF) plays a central role in the cellular response to hypoxia and is negatively regulated under normoxic conditions by prolyl hydroxylase domain-containing proteins (PHDs), also referred to as HIF prolyl hydroxylases (HIF-PHs). HIF-PH inhibitors induce erythropoietin (EPO) expression by activating HIF and are widely used for the treatment of renal anemia; however, their effects on intraocular vascular endothelial growth factor (VEGF) expression remain unclear. In this study, we examined the effects of all five HIF-PH inhibitors (roxadustat, daprodustat, vadadustat, enarodustat, and molidustat) on Vegfa expression in the retina in mice. C57BL/6 J mice were orally administered each inhibitor. Six hours after administration, the kidney, retina, and liver were collected, and transcription levels were quantified by real-time reverse transcription PCR (real-time RT-PCR). Renal Epo transcription was significantly increased by molidustat (P < 0.01), roxadustat (P < 0.01), and enarodustat (P < 0.05) significantly increased renal Epo transcription. Retinal Vegfa transcription was significantly increased by four inhibitors (P < 0.01), with molidustat showing no significant effect. In the liver, Vegfa transcription was increased by daprodustat (P < 0.05) and vadadustat (P < 0.01). No significant correlation was observed between renal Epo and retinal Vegfa transcription levels for any of the HIF-PH inhibitors. These findings indicate that HIF-PH inhibitors differentially regulate hypoxia-responsive genes across tissues and suggest that their potential effects on retinal Vegfa transcription should be considered when evaluating their ocular safety.