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.
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BibTeX
@article{hoshino2026effects,
title = {{Effects of clinically available HIF-PH inhibitors on retinal Vegfa transcription}},
author = {Junki Hoshino and Kazuki Irie and Akimitsu Konishi and Hideo Akiyama and Yoji Andrew Minamishima},
journal = {Scientific Reports},
year = {2026},
month = oct,
doi = {10.1038/s41598-026-73839-3},
url = {https://www.nature.com/articles/s41598-026-73839-3},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Effects of clinically available HIF-PH inhibitors on retinal Vegfa transcription
AU - Junki Hoshino
AU - Kazuki Irie
AU - Akimitsu Konishi
AU - Hideo Akiyama
AU - Yoji Andrew Minamishima
PY - 2026
DA - 2026/10/22
JO - Scientific Reports
DO - 10.1038/s41598-026-73839-3
UR - https://www.nature.com/articles/s41598-026-73839-3
AB - 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.
SN - 2045-2322
ER -