• Call for Physical Sciences Papers
  • Sign-up for PNAS eTOC Alerts

Comparative systems pharmacology of HIF stabilization in the prevention of retinopathy of prematurity

  1. Jonathan E. Searsa,b,1
  1. aCole Eye Institute, Cleveland Clinic, Cleveland, OH 44195;
  2. bDepartment of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195;
  3. cYorg Corporation, Plano, TX 75093;
  4. dDepartment of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065;
  5. eImageIQ Inc., Cleveland, OH 44128;
  6. fInstitute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH 44106
  1. Edited by Gregg L. Semenza, Johns Hopkins University School of Medicine, Baltimore, MD, and approved March 18, 2016 (received for review November 24, 2015)

Significance

In all premature births, oxygen supplementation is a necessary life-sustaining measure, but unfortunately for these high-risk babies, oxygen toxicity may adversely and permanently affect the retina. Pharmacological activation of the hypoxia-inducible factor (HIF) pathway can prevent experimental oxygen-induced retinopathy and thus has the potential to prevent blindness in 100,000 children annually. Comprehensive analysis of liver and retinal transcriptomes after HIF stabilization demonstrates that select small molecules, given systemically, protect the retina by two pathways: stimulating the liver to secrete angiogenic hepatokines or locally stimulating retinal protection. These findings support a low dose, intermittent, systemic approach for preventing oxygen induced injury to premature infants.

Abstract

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.

Footnotes

  • ?1To whom correspondence should be addressed. Email: searsj{at}ccf.org.
  • Author contributions: G.H., S.Y., R.B.S., and J.E.S. designed research; G.H., S.Y., A.R.S., R.B., K.C., and J.E.S. performed research; A.V. and E.R.C. contributed new reagents/analytic tools; G.H., B.G., A.R.S., A.V., E.R.C., R.B.S., and J.E.S. analyzed data; and G.H. and J.E.S. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE74170; NCBI tracking system no. 17567121).

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1523005113/-/DCSupplemental.

Online Impact