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Charandeep Singh, Amit Sharma, George Hoppe, Henri Brunengraber, Jonathan E Sears; Serine metabolism is a key pathway involved in the prevention of oxygen-induced retinopathy by Roxadustat. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5464.
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We have previously demonstrated that the hypoxia inducible factor prolyl hydroxylase inhibitor Roxadustat prevents oxygen-induced retinopathy (OIR) in newborn mice. The protected phenotype was associated with transcriptional upregulation of the glycolytic pathway in the retina. To understand why metabolic plasticity is associated with protection, we investigated Roxadustat’s effect on the retinal metabolome during hyperoxia.
Wild-type C57BL/6 pups were subjected to room air or 75% oxygen and given i.p. Roxadustat or PBS at postnatal day 6 (P6), P8 and P10. Retinas were harvested and immediately frozen 6 hr after the last injection. Polar metabolites were extracted by chloroform/methanol/water separation, dried under vacuum at -4°C, derivatized using methoxyamine/pyridine and MSTFA and analyzed using full scan GC/MS. Data were interpreted in the Metabolite Detector software using in-house generated library and Golm Metabolome Database.
Hyperoxia caused global changes in metabolite content in the retina of P10 pups. This included downregulation of lactate, glutamate and serine and upregulation of methionine. Many other members of serine utilization pathway were also affected, i.e., glycine, hypoxanthine, hypotaurine, methionine, and a few purines and pyrimidines. Roxadustat administration brought these metabolites back to near normal levels as measured in normoxia without reaching supra-normal levels.
Metabolic profiles of hyperoxic retina reveled significant changes in the pathway of serine catabolism and of closely associated tetrahydrofolate and methionine cycles. Roxadustat treatment normalized levels of the affected amino acids. Given the importance of the serine, one-carbon and transsulfuration pathways in neurodevelopment as well as in antioxidant defense, Roxadustat may mediate protection from oxygen toxicity by increasing retinal serine concentrations.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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