Sufficient liver erythropoietin synthesis is induced in hemodialysis patients not requiring erythropoiesis-stimulating agents

Yanagawa, Takamoto; Hirayama, Aki; Osada, Kayo; Kuno, Akihiro; Takahashi, Satoru

doi:10.5414/cn110749

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“…Moreover, in patients with kidney disease who require hemodialysis but not ESA, the contribution of liver-derived EPO increases to almost half of plasma EPO. 10 Therefore, for renal anemia treatment, it may be plausible to pharmacologically induce hepatic EPO production instead of in injured kidneys, although the efficacy is predicted to be low compared with renal EPO induction. In this regard, HIF-PHIs specifically targeting livers have been developed to avoid potential risks associated with pleiotropic and undesired effects induced by systemic HIF activation.…”

Section: Discussionmentioning

confidence: 99%

“… 5 , 6 , 7 HIFα proteins are hydroxylated by prolyl-hydroxylase domain–containing proteins (PHDs) and then degraded through the ubiquitin-proteasome pathway under normal oxygen conditions (normoxia). 8 , 9 , 10 Because PHDs require oxygen molecules for their catalytic activity, hypoxia inactivates PHDs and stabilizes HIFα proteins as active transcription factors.…”

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: Discussionmentioning

confidence: 99%