Esterification promotes the intracellular accumulation of roxadustat, an activator of hypoxia-inducible factors, to extend its effective duration

Nakai, Taku; Saigusa, Daisuke; Iwamura, Yuma; Matsumoto, Yotaro; Umeda, Keiko; Kato, Koichiro; Yamaki, Hayato; Tomioka, Y.; Hirano, Ikuo; Koshiba, S.; Yamamoto, Masayuki; Suzuki, Norio

doi:10.1016/j.bcp.2022.114939

Cited by 7 publications

(7 citation statements)

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“…To detect the apparent effects of HIF-PHIs in mice, roxadustat was administered at a higher dose (200 mg/kg) than GSK360A (50 mg/kg), which is a research reagent with higher efficacy than medical reagents such as roxadustat. 16 Both HIF-PHIs swiftly induced plasma EPO concentrations in the mutant mice, 6 hours after administration ( Figure 1 A). However, the induced concentrations were comparable with those in normal mice and 50- to 100-fold lower than those in the control mice injected with HIF-PHIs.…”

Section: Resultsmentioning

confidence: 95%

“…Mice were intraperitoneally injected with GSK360A (50 mg/kg body weight; Toronto Research Chemicals, Toronto, ON) or roxadustat (200 mg/kg; 5A Pharmatech, Hong Kong) after reconstitution with water containing glucose (2% w/v) and NaOH (0.5 mol/L). 15 , 16 For continuous administration, GSK360A (50 mg/kg) was injected daily for 5 days.…”

Section: Methodsmentioning

confidence: 99%

“… 11 , 12 In fact, in situ hybridization of mouse tissues demonstrated that HIF-PHIs induce Epo gene expression in REP cells but not in other cell types, under either healthy or disease conditions. 15 , 16 , 17 …”

Section: Introductionmentioning

confidence: 99%

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Drugs activating hypoxia-inducible factors correct erythropoiesis and hepcidin levels via renal EPO induction in mice

et al. 2023

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The erythroid growth factor erythropoietin (EPO) is mainly produced by the kidneys in adult mammals and induces expansion of erythroid cells and iron use for hemoglobin synthesis. The liver also produces EPO at a lower level than the kidneys. Renal and hepatic EPO production is fundamentally regulated by hypoxia-inducible transcription factors (HIFs) in a hypoxia/anemia-inducible manner. Recently, small compounds that activate HIFs and EPO production in the kidneys by inhibiting HIF-prolyl hydroxylases (HIF-PHIs) have been launched to treat EPO-deficiency anemia in patients suffering from kidney disease. However, the roles of the liver in the HIF-PHI-mediated induction of erythropoiesis and iron mobilization remain controversial. Here, to elucidate the liver contributions to the therapeutic effects of HIF-PHIs, genetically modified mouse lines lacking renal EPO-production ability were analyzed. In the mutant mice, HIF-PHI administration marginally increased plasma EPO concentrations and peripheral erythrocytes by inducing hepatic EPO production. The effects of HIF-PHIs on the mobilization of stored iron and on the suppression of hepatic hepcidin, an inhibitory molecule for iron release from iron-storage cells, were not observed in the mutant mice. These findings demonstrate that adequate induction of EPO mainly in the kidney is essential for achieving the full therapeutic effects of HIF-PHIs, which include hepcidin suppression. The data also show that HIF-PHIs directly induce the expression of duodenal genes related to dietary iron intake. Additionally, hepatic EPO induction is considered to partially contribute to the erythropoietic effects of HIF-PHIs but to be insufficient to compensate for the abundant EPO induction by the kidneys.

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Section: Resultsmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

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Drugs activating hypoxia-inducible factors correct erythropoiesis and hepcidin levels via renal EPO induction in mice

et al. 2023

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“…Regarding mechanism, roxadustat enhances the activity of HIF transcription by inhibiting the activity of hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) and reducing HIF-alpha degradation [21,22]. Several studies have demonstrated increased levels of HIF-1α expression in cells or mice after being treated with roxadustat [16,23,24]. In rodents, roxadustat and its analogues have shown significant effectiveness in reducing cardiac hypertrophy [15,16,25].…”

Section: Discussionmentioning

confidence: 99%

Roxadustat reduces left ventricular mass index compared to rHuEPO in haemodialysis patients in a randomized controlled trial

Tan,

Wang,

Sun

et al. 2024

J Intern Med

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BackgroundLeft ventricular hypertrophy (LVH) is highly prevalent in haemodialysis (HD) patients and is associated with an increased risk of death. Roxadustat and recombinant human erythropoietin (rHuEPO, abbreviated as EPO) are the main treatment strategies for renal anaemia in HD patients, but it has not been clear whether there is a difference in their effect on LVH.MethodsIn this multi‐centre, prospective, randomized trial of 12‐month duration, study participants were randomized in a 1:1 ratio to the roxadustat group or the EPO group. The doses of both treatment regimens were adjusted so that the patients had a haemoglobin level of 10.0–12.0 g per dL. The primary study endpoint was the change from baseline to 12 months in the left ventricular mass index (LVMI, g/m2) measured by echocardiography.ResultsIn total, 114 patients were enrolled. The mean age was 50 years, and the median dialysis duration was 33 months. Sixty‐one patients were men, and 24 were diabetic. LVMI decreased from 116.18 ± 27.84 to 110.70 ± 25.74 g/m2 in the roxadustat group. However, it increased from 109.35 ± 23.41 to 114.99 ± 28.46 g/m2 in the EPO group, with a significant difference in the change in LVMI between the two groups [−5.48 (−11.60 to 0.65) vs. 5.65 (0.74 to 10.55), p < 0.05]. Changes in left ventricular mass, end‐diastolic volume and 6‐min walk test seemed superior in the roxadustat group. There were no significant differences in other cardiac geometry, biochemical parameters and major adverse cardiovascular events between the two groups.ConclusionsCompared to EPO, roxadustat is more helpful in the regression of LVH in HD patients.

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“…Therefore, HIF-PH inhibitors (PHD inhibitors) have been developed to block over-activated PHDs and are currently used for treatment of renal anemia. (43)(44)(45)(46) Further progression of myofibroblastic transformation silences EPO and EPAS1 (HIF2α) gene expression by inducing DNA methylation in the promoter regions of these genes. (42,43,47) Epigenetic silencing means that HIF-PH inhibitors cannot induce EPO gene expression in terminally mature renal myofibroblasts due to a lack of HIF2α synthesis at the transcriptional level.…”

Section: Rep Cells Are Transformed Into Myofibroblasts Thereby Promot...mentioning

confidence: 99%

Crosstalk between oxygen signaling and iron metabolism in renal interstitial fibroblasts

Suzuki,

Iwamura,

Kato

et al. 2024

J. Clin. Biochem. Nutr.

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To maintain the oxygen supply, the production of red blood cells (erythrocytes) is promoted under low-oxygen conditions (hypoxia). Oxygen is carried by hemoglobin in erythrocytes, in which the majority of the essential element iron in the body is contained. Because iron metabolism is strictly controlled in a semi-closed recycling system to protect cells from oxidative stress caused by iron, hypoxia-inducible erythropoiesis is closely coordinated by regulatory systems that mobilize stored iron for hemoglobin synthesis. The erythroid growth factor erythropoietin (EPO) is mainly secreted by interstitial fibroblasts in the renal cortex, which are known as renal EPO-producing (REP) cells, and promotes erythropoiesis and iron mobilization. Intriguingly, EPO production is strongly induced by hypoxia through iron-dependent pathways in REP cells. Here, we summarize recent studies on the network mechanisms linking hypoxia-inducible EPO production, erythropoiesis and iron metabolism. Additionally, we introduce disease mechanisms related to disorders in the network mediated by REP cell functions. Furthermore, we propose future studies regarding the application of renal cells derived from the urine of kidney disease patients to investigate the molecular pathology of chronic kidney disease and develop precise and personalized medicine for kidney disease.

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Esterification promotes the intracellular accumulation of roxadustat, an activator of hypoxia-inducible factors, to extend its effective duration

Cited by 7 publications

References 53 publications

Drugs activating hypoxia-inducible factors correct erythropoiesis and hepcidin levels via renal EPO induction in mice

Drugs activating hypoxia-inducible factors correct erythropoiesis and hepcidin levels via renal EPO induction in mice

Roxadustat reduces left ventricular mass index compared to rHuEPO in haemodialysis patients in a randomized controlled trial

Crosstalk between oxygen signaling and iron metabolism in renal interstitial fibroblasts

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