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

Nakai, Taku; Iwamura, Yuma; Kato, Koichiro; Hirano, Ikuo; Matsumoto, Yotaro; Tomioka, Y.; Yamamoto, Masayuki; Suzuki, Norio

doi:10.1182/bloodadvances.2023009798

Cited by 9 publications

(2 citation statements)

References 63 publications

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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 – 46 )…”

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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“…Therefore, HIF-PH inhibitors (PHD inhibitors) have been developed to block over-activated PHDs and are currently used for treatment of renal anemia. ( 43 – 46 )…”

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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“…However, it has been reported that hepcidin is not a direct transcriptional target of HIF [ 21 ]. The mechanism by which hepcidin is decreased by HIF-PHIs has been attributed primarily to increased production of erythroferron due to increased hematopoiesis [ 22 ].…”

Section: Advantages Of and Potential Issues With Hif-phismentioning

confidence: 99%

Growing concerns about using hypoxia-inducible factor prolyl hydroxylase inhibitors for the treatment of renal anemia

Nakanishi,

Kuragano

2024

Clinical Kidney Journal

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Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have emerged as a novel therapeutic class for treating anemia in patients with chronic kidney disease. Small molecule analogs of α-ketoglutarate (AKG), an essential substrate for 2-oxoglutarate-dependent dioxygenases (2-OGDDs), including prolyl hydroxylase domain proteins (PHDs), inhibit PHD pharmacologically and thereby prevent HIF degradation. HIF stabilization alleviates anemia through several stimulatory effects on erythropoiesis, but it also affects the expression of many anemia-unrelated genes whose protein products exert important functions in vivo. Therefore, the pleiotropic effects of HIF stabilization under normoxic conditions deserve to be examined in more detail. Specifically, we believe that particular attention should be given to epigenetic modifications among the various AKG-based metabolic systems that may be altered by HIF-PHIs. It is noteworthy that AKG has been reported to exert health-protective actions. AKG-based metabolic systems include enzymes associated with the tricarboxylic acid cycle and amino acid metabolism, as well as 2-OGDD-mediated processes, which play important roles in many biological reactions. In this review, we examine the multifaceted effects of HIF-PHIs, encompassing not only their on-target effect of HIF stabilization but also their off-target inhibitory effects on various AKG-based metabolic systems. Furthermore, we examine its potential relevance to cardiovascular complications, based on clinical and animal studies suggesting its involvement in vascular calcification, thrombogenesis, and heart failure. In conclusion, although HIF-PHIs offer a promising avenue for anemia treatment in CKD patients, their broader impact on multiple biological systems raises substantial concerns. The intricate interplay between HIF stabilization, AKG competition, and cardiovascular complications warrants extensive, long-term investigations to ensure the safety and usefulness of HIF-PHIs in clinical practice.

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A preliminary study of roxadustat in the treatment of aplastic anemia patients with inadequate erythroid responses

Shi,

Zhao,

Liang

et al. 2024

Ann Hematol

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Some aplastic anemia(AA) patients only have partial hematological responses after immunosuppressive therapy. Failure to achieve complete normalization of blood counts, particularly hemoglobin, will reduce their quality of life. This open-label pilot study was conducted to evaluate the efficacy and safety of roxadustat in this setting. A total of 14 patients with AA who had inadequate erythroid response after immunosuppressive therapy were included in the study. The primary efficacy endpoint was hemoglobin response at week 8 after roxadustat treatment. The median duration of roxadustat therapy was 14 (4–30) weeks, with 12 patients receiving roxadustat for ≥ 8 weeks. At week 8, nine patients (9/14, 64.3%) had their hemoglobin rising for at least 15 g/L, with two patients (2/14, 14.3%) achieving normal hemoglobin levels. By the last follow-up, hemoglobin responses were observed in 10 patients (10/14, 71.4%), with 4 patients(4/14, 28.6%) having normal hemoglobin levels. Roxadustat was tapered or discontinued in four responded patients; one relapsed after 12 weeks of tapering, and three maintained their response. Four patients (4/14, 28.6%) experienced mild adverse effects during therapy. Roxadustat is safe and well tolerated by patients with AA. Treatment with the hypoxia-inducible factor prolyl hydroxylase inhibitor improves hemoglobin levels in AA patients with inadequate erythroid responses.

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

Cited by 9 publications

References 63 publications

Crosstalk between oxygen signaling and iron metabolism in renal interstitial fibroblasts

Crosstalk between oxygen signaling and iron metabolism in renal interstitial fibroblasts

Growing concerns about using hypoxia-inducible factor prolyl hydroxylase inhibitors for the treatment of renal anemia

A preliminary study of roxadustat in the treatment of aplastic anemia patients with inadequate erythroid responses

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