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Updates on Erythropoietin

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 31 August 2024 | Viewed by 2620

Special Issue Editor

Division of Internal Medicine, Kitasato University Medical Center, 6-100 Arai, Kitamoto, Saitama 364-8501, Japan
Interests: erythropoietin; hypoxia; renal anemia; acid-base balance; hypertension

Special Issue Information

Dear Colleagues, 

Red blood cells carry oxygen to all organs in the body. Hypoxia and anemia cause cell damage and finally result in cell death. Erythropoietin (Epo) is produced via the activation of HIF2a and downregulation of PHD2 by hypoxia and anemia. Erythropoiesus-stimulating agent (ESA) and PHD inhibitors were used to substitute the erythrpoietic effects of Epo for patients with renal anemia. Epo has many effects on cellular function other than the production of blood cells. After many large-scale studies, ESAs were found not to have renoprotective effects. However, PHD inhibitors have renoprotective effects, especially in cases of ishchemic reperfusion injury. Although exogenous Epo (ESAs) does not have renoprotective effects, endogenous Epo produced by PHD inhibitors has renoprotective effects, suggesting that the HIF-PHD-Epo cascade is related to cell survival. The purpose of this Special Issue is to gather various data on the HIF-PHD-Epo cascade to discuss the role of endogenous Epo in cell survival against hypoxia.

Dr. Hiroshi Nonoguchi
Guest Editor

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Keywords

  • erythropoietin (Epo)
  • hypoxia
  • hypoxia-inducible factor (HIF)
  • prolyl hydroxylase domain (PHD) inhibitor
  • chronic kidney disease (CKD)
  • anemia
  • erythropoiesus-stimulating agent (ESA)

Published Papers (3 papers)

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Research

13 pages, 9927 KiB  
Article
High Ferritin Is Not Needed in Hemodialysis Patients: A Retrospective Study of Total Body Iron and Oral Iron Replacement Therapy
by Chie Ogawa, Ken Tsuchiya, Naohisa Tomosugi and Kunimi Maeda
Int. J. Mol. Sci. 2024, 25(3), 1508; https://doi.org/10.3390/ijms25031508 - 25 Jan 2024
Viewed by 566
Abstract
In vivo iron levels can be adjusted through intestinal iron absorption to be maintained at a suitable level; however, optimal iron levels in hemodialysis (HD) patients are unclear. In this study, we investigated total body iron (TBI), calculated as the sum of red [...] Read more.
In vivo iron levels can be adjusted through intestinal iron absorption to be maintained at a suitable level; however, optimal iron levels in hemodialysis (HD) patients are unclear. In this study, we investigated total body iron (TBI), calculated as the sum of red blood cell (RBC) iron and iron stores, during courses of low-dose oral iron replacement therapy, and evaluated in vivo iron sufficiency and its indicators in HD patients. We analyzed data on 105 courses of low-dose iron replacement therapy administered to 83 patients on maintenance HD over 7 months. We evaluated changes in TBI, RBC iron, and iron stores from the initiation of treatment to month 7 in two groups of patients, namely, iron-therapy responders and non-responders. TBI showed significant increases until month 4 and plateaued thereafter in iron-therapy responders, and tended to increase and then reached a similar plateau in non-responders (month 7: 1900 ± 447 vs. 1900 ± 408 mg). Steady-state TBI was strongly correlated with body surface area (y = 1628.6x − 791.91, R2 = 0.88, p < 0.001). We observed constant TBI during oral iron replacement therapy suggesting the activation of a “mucosal block”. The results suggest that body surface area has utility for estimating the required TBI with regression equations. Full article
(This article belongs to the Special Issue Updates on Erythropoietin)
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14 pages, 3876 KiB  
Article
Tubular Endogenous Erythropoietin Protects Renal Function against Ischemic Reperfusion Injury
by Yukiko Yasuoka, Yuichiro Izumi, Takashi Fukuyama, Tomomi Oshima, Taiga Yamazaki, Takayuki Uematsu, Noritada Kobayashi, Masayoshi Nanami, Yoshitaka Shimada, Yasushi Nagaba, Masashi Mukoyama, Jeff M. Sands, Noriko Takahashi, Katsumasa Kawahara and Hiroshi Nonoguchi
Int. J. Mol. Sci. 2024, 25(2), 1223; https://doi.org/10.3390/ijms25021223 - 19 Jan 2024
Viewed by 518
Abstract
Many large-scale studies show that exogenous erythropoietin, erythropoiesis-stimulating agents, lack any renoprotective effects. We investigated the effects of endogenous erythropoietin on renal function in kidney ischemic reperfusion injury (IRI) using the prolyl hydroxylase domain (PHD) inhibitor, Roxadustat (ROX). Four h of hypoxia (7% [...] Read more.
Many large-scale studies show that exogenous erythropoietin, erythropoiesis-stimulating agents, lack any renoprotective effects. We investigated the effects of endogenous erythropoietin on renal function in kidney ischemic reperfusion injury (IRI) using the prolyl hydroxylase domain (PHD) inhibitor, Roxadustat (ROX). Four h of hypoxia (7% O2) and 4 h treatment by ROX prior to IRI did not improve renal function. In contrast, 24–72 h pretreatment by ROX significantly improved the decline of renal function caused by IRI. Hypoxia and 4 h ROX increased interstitial cells-derived Epo production by 75- and 6-fold, respectively, before IRI, and worked similarly to exogenous Epo. ROX treatment for 24–72 h increased Epo production during IRI by 9-fold. Immunohistochemistry revealed that 24 h ROX treatment induced Epo production in proximal and distal tubules and worked similarly to endogenous Epo. Our data show that tubular endogenous Epo production induced by 24–72 h ROX treatment results in renoprotection but peritubular exogenous Epo production by interstitial cells induced by hypoxia and 4 h ROX treatment did not. Stimulation of tubular, but not peritubular, Epo production may link to renoprotection. Full article
(This article belongs to the Special Issue Updates on Erythropoietin)
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14 pages, 2244 KiB  
Article
Changes in Metabolomic Profiles Induced by Switching from an Erythropoiesis-Stimulating Agent to a Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor in Hemodialysis Patients: A Pilot Study
by Kimio Watanabe, Emiko Sato, Eikan Mishima, Shinobu Moriya, Takuma Sakabe, Atsuya Sato, Momoko Fujiwara, Takuya Fujimaru, Yugo Ito, Fumika Taki, Masahiko Nagahama, Kenichi Tanaka, Junichiro James Kazama and Masaaki Nakayama
Int. J. Mol. Sci. 2023, 24(16), 12752; https://doi.org/10.3390/ijms241612752 - 13 Aug 2023
Viewed by 1124
Abstract
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of medications for managing renal anemia in patients with chronic kidney disease (CKD). In addition to their erythropoietic activity, HIF-PHIs exhibit multifaceted effects on iron and glucose metabolism, mitochondrial metabolism, and angiogenesis through [...] Read more.
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of medications for managing renal anemia in patients with chronic kidney disease (CKD). In addition to their erythropoietic activity, HIF-PHIs exhibit multifaceted effects on iron and glucose metabolism, mitochondrial metabolism, and angiogenesis through the regulation of a wide range of HIF-responsive gene expressions. However, the systemic biological effects of HIF-PHIs in CKD patients have not been fully explored. In this prospective, single-center study, we comprehensively investigated changes in plasma metabolomic profiles following the switch from an erythropoiesis-stimulating agent (ESA) to an HIF-PHI, daprodustat, in 10 maintenance hemodialysis patients. Plasma metabolites were measured before and three months after the switch from an ESA to an HIF-PHI. Among 106 individual markers detected in plasma, significant changes were found in four compounds (erythrulose, n-butyrylglycine, threonine, and leucine), and notable but non-significant changes were found in another five compounds (inositol, phosphoric acid, lyxose, arabinose, and hydroxylamine). Pathway analysis indicated decreased levels of plasma metabolites, particularly those involved in phosphatidylinositol signaling, ascorbate and aldarate metabolism, and inositol phosphate metabolism. Our results provide detailed insights into the systemic biological effects of HIF-PHIs in hemodialysis patients and are expected to contribute to an evaluation of the potential side effects that may result from long-term use of this class of drugs. Full article
(This article belongs to the Special Issue Updates on Erythropoietin)
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