期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 18, 页码 E2516-E2525出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1523005113
关键词
HIF; BPD; prolyl hydroxylase inhibition; Roxadustat; ROP
资金
- Research to Prevent Blindness Unrestricted Challenge Grant from the E. Matilda Ziegler Foundation for the Blind
- Hartwell Foundation Collaborative Biomedical Research Fellowship
- NIH [R01EY024972]
- Genomics Core Facility of the Case Western Reserve University School of Medicine Genetics and Genome Sciences Department and Case Comprehensive Cancer Center [P30CA043703]
Retinopathy of prematurity (ROP) causes 100,000 new cases of childhood blindness each year. ROP is initiated by oxygen supplementation necessary to prevent neonatal death. We used organ systems pharmacology to define the transcriptomes of mice that were cured of oxygen-induced retinopathy (OIR, ROP model) by hypoxia-inducible factor (HIF) stabilization via HIF prolyl hydroxylase inhibition using the isoquinolone Roxadustat or the 2-oxoglutarate analog dimethyloxalylglycine (DMOG). Although both molecules conferred a protective phenotype, gene expression analysis by RNA sequencing found that Roxadustat can prevent OIR by two pathways: direct retinal HIF stabilization and induction of aerobic glycolysis or indirect hepatic HIF-1 stabilization and increased serum angiokines. As predicted by pathway analysis, Roxadustat rescued the hepatic HIF-1 knockout mouse from retinal oxygen toxicity, whereas DMOG could not. The simplicity of systemic treatment that targets both the liver and the eye provides a rationale for protecting the severely premature infant from oxygen toxicity.
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