Serine and 1-carbon metabolism are required for HIF-mediated protection against retinopathy of prematurity

Singh, Charandeep; Hoppe, George; Tran, Vincent; McCollum, Leah; Bolok, Youstina; Song, Weilin; Sharma, Amit; Brunengraber, Henri; Sears, Jonathan E.

doi:10.1172/jci.insight.129398

Cited by 40 publications

(59 citation statements)

References 46 publications

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“…The urinary excretion rates of FG-2216 and molidustat, which induced renal EPO, were 11% and 1.4%-3.6%, respectively (Bernhardt et al, 2010;Böttcher et al, 2018). In contrast, the urinary excretion rate of TP0463518 was almost zero, and DMOG, which dominantly induced hepatic EPO, was metabolized in the liver (Hamada et al, 2018;Singh et al, 2019). Taking these points into consideration, a compound in the tubular might be delivered to the tubulointerstitium, and then the compound would exert EPO-producing effect in the kidney.…”

Section: Discussionmentioning

confidence: 99%

TP0463518, a Novel Prolyl Hydroxylase Inhibitor, Specifically Induces Erythropoietin Production in the Liver

Kato

Ochiai

Takano

et al. 2019

J Pharmacol Exp Ther

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Prolyl hydroxylase (PHD) 1/2/3 pan inhibitors are known to potentially induce erythropoietin (EPO) production in both the kidney and liver. The 2-[[1-[[6-(4-chlorophenoxy)pyridin-3-yl] methyl]-4-hydroxy-6-oxo-2,3-dihydropyridine-5-carbonyl]amino] acetic acid (TP0463518) is a novel PHD 1/2/3 pan inhibitor; however, the main source of EPO production after TP0463518 administration remained to be investigated. We examined the effect of TP0463518 in inducing EPO production in the kidney and liver by measuring the hypoxia-inducible factor 2a (HIF-2a), EPO mRNA, and serum EPO levels in normal and bilaterally nephrectomized rats. Furthermore, we examined whether liverderived EPO improved anemia in 5/6 nephrectomized (5/6 Nx) rats. TP0463518 scarcely increased the HIF-2a and EPO mRNA expression levels in the kidney cortex, whereas oral administration of TP0463518 at 40 mg/kg dramatically increased the HIF-2a level from 0.27 to 1.53 fmol/mg and the EPO mRNA expression level by 1300-fold in the livers of healthy rats. After administration of TP0463518 at 20 mg/kg, the total EPO mRNA expression level in the whole liver was 22-fold that in the whole kidney. In bilaterally nephrectomized rats, TP0463518 raised the serum EPO concentration from 0 to 180 pg/ml at 20 mg/kg. Furthermore, repeated administration of TP0463518 at 10 mg/kg increased the reticulocyte count in 5/6 Nx rats on day 7 and raised the hemoglobin level on day 14. The present study revealed that TP0463518 specifically induced EPO production in the liver and improved anemia. The characteristic feature of TP0463518 would lead to not only a more detailed understanding of the PHD-HIF2a-EPO pathway in erythropoiesis, but a new therapeutic alternative for renal anemia. SIGNIFICANCE STATEMENT Prolyl hydroxylase (PHD) 1/2/3 pan inhibitors are known to potentially induce erythropoietin (EPO) production in both the kidney and liver; however, their effects on renal EPO production have been shown to vary depending on the experimental conditions. The authors found that 2-[[1-[[6-(4-chlorophenoxy)pyridin-3-yl]methyl]-4-hydroxy-6-oxo-2,3-dihydropyridine-5-carbonyl] amino]acetic acid (TP0463518), a PHD 1/2/3 pan inhibitor, specifically induced EPO production in the liver and that the liver-derived EPO was pharmacologically effective. Investigation of the effects of TP0463518 may pave the way for the development of a new therapeutic alternative for renal anemia patients.

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Section: Discussionmentioning

confidence: 99%

TP0463518, a Novel Prolyl Hydroxylase Inhibitor, Specifically Induces Erythropoietin Production in the Liver

Kato

Ochiai

Takano

et al. 2019

J Pharmacol Exp Ther

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“…It is worth noting, however, that the converse is possibly true during development. In a hyperoxic mouse model of retinopathy of prematurity, elevated aerobic glycolysis in response to pharmacological HIF activation may contribute to retinal neuroprotection 141,142 . Whether endogenous HIF is important in driving glycolysis during development is unclear.…”

Section: Hypoxia‐inducible Factormentioning

confidence: 99%

Power to see—Drivers of aerobic glycolysis in the mammalian retina: A review

Haydinger

Kittipassorn

Peet

2020

Clinical Exper Ophthalmology

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The mammalian retina converts most glucose to lactate rather than catabolizing it completely to carbon dioxide via oxidative phosphorylation, despite the availability of oxygen. This unusual metabolism is known as aerobic glycolysis or the Warburg effect. Molecules and pathways that drive aerobic glycolysis have been identified and thoroughly studied in the context of cancer but remain relatively poorly understood in the retina. Here, we review recent research on the molecular mechanisms that underly aerobic glycolysis in the retina, focusing on key glycolytic enzymes including hexokinase 2 (HK2), pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA). We also discuss the potential involvement of cell signalling and transcriptional pathways including phosphoinositide 3-kinase (PI3K) signalling, fibroblast growth factor receptor (FGFR) signalling, and hypoxia-inducible factor 1 (HIF-1), which have been implicated in driving aerobic glycolysis in the context of cancer.

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“…We have evaluated the strategy of stabilizing HIF during hyperoxia using protection against vascular obliteration and pathological angiogenesis measured in retinal flatmounts as one metric of efficacy. In retinas protected against retinopathy we find (1) no liver or kidney toxicity, (2) 85-100% reduction of oxygen induced retinal vasoobliteration and neovascularization in mice and rats, (3) normalization of the electroretinogram in hyperoxia, (4) normalization of ocular coherence tomography, (5) a cadre of serum biomarkers secreted by liver, and (6) and a metabolic switch to upregulate the urea cycle and 1C/serine metabolism (Hoppe et al, 2014(Hoppe et al, , 2016Singh et al, 2019Singh et al, , 2020. We observed that when using DMOG, hepatic HIF-1 was necessary and sufficient to prevent OIR but that Roxadustat could partially overcome hepatic HIF-1 ablation because it also targeted the retina.…”

Section: Introductionmentioning

confidence: 88%

“…A very well-defined model of ROP (Smith et al, 1994) was utilized for creating oxygen-induced retinopathy in newborn mouse pups by exposing them to 75% oxygen from P7 to P12 and analyzing retinal vasculature at P17 by staining dissected and fixed retina with Alexa568-conjugated Isolectin GS-IB4 from Griffonia Simplicifolia (Life Technologies). A detailed procedure for retina dissection, staining, imaging and vascular analysis was published elsewhere (Singh et al, 2019). Testing the drug potency to prevent OIR was carried out according to the standard protocol, i.e., 3 sequential intraperitoneal injections at P6, P8, and P10 as described (Sears et al, 2008).…”

Section: Oir Model and Retinal Vasculature Analysismentioning

confidence: 99%

Rank Order of Small Molecule Induced Hypoxiamimesis to Prevent Retinopathy of Prematurity

Hoppe

Bolok

McCollum

et al. 2020

Front. Cell Dev. Biol.

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Here we rank order small molecule inhibitors of hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) using severity of oxygen induced retinopathy (OIR) as an outcome measure. Dose response analyses in cell cultures of hepatoma (Hep3B), retinal Müller cells (MIO-M1) and primary retinal endothelial cells were conducted to evaluate potency by comparing dose to HIF-1,2 protein levels by western blotting. In vivo dose response was determined using the luciferase-transgene HIF reporter (luc-ODD). Each compound was placed in rank order by their ability to reduce neovascularization and capillary drop out in the OIR mouse model. An Epas1 KO confined to retinal Müller cells was used to determine whether successful protection by HIF stabilization requires HIF-2. Two candidate small molecules can prevent OIR by stabilizing HIF-1 to prevent oxygen induced growth attenuation and vascular obliteration. Müller cell HIF-2, the mediator of pathologic retinal angiogenesis, is not required for protection. The lack of dependence on Müller cell HIF-2 predicts that inhibition of HIF PHD will not drive pathological angiogenesis.

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Serine and 1-carbon metabolism are required for HIF-mediated protection against retinopathy of prematurity

Cited by 40 publications

References 46 publications

TP0463518, a Novel Prolyl Hydroxylase Inhibitor, Specifically Induces Erythropoietin Production in the Liver

TP0463518, a Novel Prolyl Hydroxylase Inhibitor, Specifically Induces Erythropoietin Production in the Liver

Power to see—Drivers of aerobic glycolysis in the mammalian retina: A review

Rank Order of Small Molecule Induced Hypoxiamimesis to Prevent Retinopathy of Prematurity

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