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Urea cycle and 1C/serine metabolism in the prevention of oxygen induced retinopathy

ABSTRACT: Untargeted metabolite profiling links the urea cycle and 1C/serine metabolism in the prevention of oxygen induced retinopathy by hepatic HIF stabilization. Premature infants require oxygen supplementation to survive that is simultaneously toxic to developing tissues. We have demonstrated that hypoxia inducible factor (HIF) stabilization during hyperoxia prevents oxygen induced retinopathy (OIR) and lung disease. Here, untargeted metabolite profiling coupled to XCMS systems biology analysis finds that serine/1C and urea cycles dominate pathway enrichment graphs. MS1 peak areas and MS2 library matches reveal 50% or more increased levels of plasma and retina serine, glycine, hypotaurine, methionine, and taurine. In addition, N-acetylglutamate increased 4-fold in serum, while orotate, citrulline, arginine, aspartate, glutamine were at least 50% increased after HIF stabilization. Targeted data analysis in vivo finds that retinal serine and glycine were derived from liver. HIF-1α2lox/2lox; albumin-cre KO had reduced levels of serine and retinal glycine. Inhibition of 1C metabolism blocked rescue by HIF stabilization. The metabolic phenotype of mice protected from OIR by HIF stabilization is dependent on hepatic serine/1C metabolism and urea cycle.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Blood

DISEASE(S): Eye Disease

SUBMITTER: Charandeep Singh

PROVIDER: ST001130 | MetabolomicsWorkbench | Thu Jan 31 00:00:00 GMT 2019

REPOSITORIES: MetabolomicsWorkbench

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Project description:Retinopathy of prematurity (ROP) is the most common cause of childhood blindness worldwide and is caused by oxygen therapy necessary to prevent mortality after premature birth. We have previously demonstrated the efficacy of systemic hypoxia inducible factor (HIF) stabilization through HIF prolyl hydroxylase inhibition (HIF PHi) in protecting retinal vasculature from oxygen toxicity in a mouse model of ROP or oxygen induced retinopathy (OIR). We definitively demonstrated that hepatic HIF-1 can be activated to confer this protection using systemic dimethyloxalylglycine (DMOG) to prevent HIF-1α degradation. In this study we compare Roxadustat, a small molecule stabilizer of HIF-1 currently in phase 3 clinical trials for increasing erythropoiesis in adult patients with chronic kidney disease, to DMOG. We demonstrate that Roxadustat induces vascular protection during hyperoxia to induce the coordinated sequential growth of retinal vasculature with a 3-fold reduction in oxygen induced capillary loss (p-=0.001). In order to define the molecular mechanism of protection, we further compared the transcriptome of both liver and retina after systemic treatment with Roxadustat or DMOG. Similar gene expression profiles were identified in liver but very different effects on transcription were found in retinal tissues because Roxadustat, in contrast to DMOG, directly targets retina, confirmed by western blot and by rescue of the hepatic HIF-1 KO, two criteria that DMOG treatment is unable to fulfill. Systems pharmacologic analysis demonstrates that Roxadustat induces typical HIF regulated genes critical to aerobic glycolysis in liver and retinal tissues whereas DMOG, acting through either secreted hepatokines or by influence of systemic DMOG, downregulates cell adhesion/extracellular matrix interaction pathways while increasing expression of histone cluster genes. Stratification of liver transcriptomes to secreted gene products again shows close consensus of hepatic genes induced by both small molecules, and includes upregulation of a plethora of angiogenic proteins such as plasminogen activator inhibitor (PAI-1), erythropoietin (EPO), and orosomucosoid 2 (ORM2). Secondary validation of these transcripts by serum ELISA confirms secretion of EPO and PAI-1 into blood from liver. These findings definitively demonstrate that HIF stabilization 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. Systems pharmacology analysis therefore explains why intermittent, low dosage of small molecule HIF stabilizers creates a profound protective phenotype, because both pathways can take advantage of cytoprotection induced by the liver and by retina synergistically. These data provide a rationale for considering low dose, intermittent systemic administration of Roxadustat, currently in phase 3 trials in adults with chronic kidney disease, to eradicate ROP in children.

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Urea cycle and 1C/serine metabolism in the prevention of oxygen induced retinopathy

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