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Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (Molidustat) stimulates erythropoietin production without hypertensive effects.

Flamme I, Oehme F, Ellinghaus P, Jeske M, Keldenich J, Thuss U - PLoS ONE (2014)

Bottom Line: Mimicking hypoxia by inhibiting HIF-PHs, thereby stabilizing HIF, is a novel treatment concept for restoring endogenous EPO production.Notably, unlike treatment with the antihypertensive enalapril, the blood pressure normalization was achieved without a compensatory activation of the renin-angiotensin system.Clinical studies are ongoing to investigate the effects of BAY 85-3934 therapy in patients with renal anemia.

View Article: PubMed Central - PubMed

Affiliation: Cardiology/Hematology, Acute Care Research, Global Drug Discovery, Bayer Pharma AG, Wuppertal, Germany.

ABSTRACT
Oxygen sensing by hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) is the dominant regulatory mechanism of erythropoietin (EPO) expression. In chronic kidney disease (CKD), impaired EPO expression causes anemia, which can be treated by supplementation with recombinant human EPO (rhEPO). However, treatment can result in rhEPO levels greatly exceeding the normal physiological range for endogenous EPO, and there is evidence that this contributes to hypertension in patients with CKD. Mimicking hypoxia by inhibiting HIF-PHs, thereby stabilizing HIF, is a novel treatment concept for restoring endogenous EPO production. HIF stabilization by oral administration of the HIF-PH inhibitor BAY 85-3934 (molidustat) resulted in dose-dependent production of EPO in healthy Wistar rats and cynomolgus monkeys. In repeat oral dosing of BAY 85-3934, hemoglobin levels were increased compared with animals that received vehicle, while endogenous EPO remained within the normal physiological range. BAY 85-3934 therapy was also effective in the treatment of renal anemia in rats with impaired kidney function and, unlike treatment with rhEPO, resulted in normalization of hypertensive blood pressure in a rat model of CKD. Notably, unlike treatment with the antihypertensive enalapril, the blood pressure normalization was achieved without a compensatory activation of the renin-angiotensin system. Thus, BAY 85-3934 may provide an approach to the treatment of anemia in patients with CKD, without the increased risk of adverse cardiovascular effects seen for patients treated with rhEPO. Clinical studies are ongoing to investigate the effects of BAY 85-3934 therapy in patients with renal anemia.

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Effects of BAY 85-3934 administration in male Wistar rats treated with gentamicin to induce renal anemia.Data are presented as means ± SEM. (A) Plasma EPO levels, and (B) kidney and (C) liver relative expression of erythropoietin (EPO) mRNA 4 h after oral administration of BAY 85-3934. Before administration, rats had been treated with vehicle or gentamicin. (n = 5 animals per group). *p<0.05, **p<0.01, and ***p<0.001 compared with vehicle group, §p<0.05 and §§p<0.001 compared with control group, t-test. (D) Kidney and (E) liver mRNA expression levels of hypoxia-inducible factor target genes relative to mean of vehicle treated animals after oral administration of BAY 85-3934 (n = 4 to 5 animals per group, error bars not shown for clarity of presentation). For definition of gene symbols, see Table 1. (F) Time-course of changes in packed cell volume (PCV) following treatment with BAY 85-3934 or vehicle (once daily, five times per week, number of animals as indicated). (G) Hemoglobin levels 7 days after start of treatment with BAY 85-3934 or vehicle at day 22 of experiment shown in (F). *p<0.05, **p<0.01, and ***p<0.001 compared with vehicle group; #p<0.05 compared with sham group; t-test.
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pone-0111838-g004: Effects of BAY 85-3934 administration in male Wistar rats treated with gentamicin to induce renal anemia.Data are presented as means ± SEM. (A) Plasma EPO levels, and (B) kidney and (C) liver relative expression of erythropoietin (EPO) mRNA 4 h after oral administration of BAY 85-3934. Before administration, rats had been treated with vehicle or gentamicin. (n = 5 animals per group). *p<0.05, **p<0.01, and ***p<0.001 compared with vehicle group, §p<0.05 and §§p<0.001 compared with control group, t-test. (D) Kidney and (E) liver mRNA expression levels of hypoxia-inducible factor target genes relative to mean of vehicle treated animals after oral administration of BAY 85-3934 (n = 4 to 5 animals per group, error bars not shown for clarity of presentation). For definition of gene symbols, see Table 1. (F) Time-course of changes in packed cell volume (PCV) following treatment with BAY 85-3934 or vehicle (once daily, five times per week, number of animals as indicated). (G) Hemoglobin levels 7 days after start of treatment with BAY 85-3934 or vehicle at day 22 of experiment shown in (F). *p<0.05, **p<0.01, and ***p<0.001 compared with vehicle group; #p<0.05 compared with sham group; t-test.

Mentions: The effect of BAY 85-3934 on the induction of endogenous EPO production was evaluated in an animal model of impaired kidney function, the gentamicin-induced kidney failure model. A mean creatinine clearance of 30% of that of untreated animals and high expression levels of several markers of acute and chronic kidney injury were indicative of substantial renal impairment in these animals. Treatment with BAY 85-3934 significantly and dose-dependently induced plasma EPO levels (Fig. 4A). Accordingly, EPO mRNA expression increased dose-dependently in kidney samples taken from these animals (Fig. 4B). The mean absolute levels of induction were lower in the gentamicin-treated animals than in the controls.


Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (Molidustat) stimulates erythropoietin production without hypertensive effects.

Flamme I, Oehme F, Ellinghaus P, Jeske M, Keldenich J, Thuss U - PLoS ONE (2014)

Effects of BAY 85-3934 administration in male Wistar rats treated with gentamicin to induce renal anemia.Data are presented as means ± SEM. (A) Plasma EPO levels, and (B) kidney and (C) liver relative expression of erythropoietin (EPO) mRNA 4 h after oral administration of BAY 85-3934. Before administration, rats had been treated with vehicle or gentamicin. (n = 5 animals per group). *p<0.05, **p<0.01, and ***p<0.001 compared with vehicle group, §p<0.05 and §§p<0.001 compared with control group, t-test. (D) Kidney and (E) liver mRNA expression levels of hypoxia-inducible factor target genes relative to mean of vehicle treated animals after oral administration of BAY 85-3934 (n = 4 to 5 animals per group, error bars not shown for clarity of presentation). For definition of gene symbols, see Table 1. (F) Time-course of changes in packed cell volume (PCV) following treatment with BAY 85-3934 or vehicle (once daily, five times per week, number of animals as indicated). (G) Hemoglobin levels 7 days after start of treatment with BAY 85-3934 or vehicle at day 22 of experiment shown in (F). *p<0.05, **p<0.01, and ***p<0.001 compared with vehicle group; #p<0.05 compared with sham group; t-test.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4230943&req=5

pone-0111838-g004: Effects of BAY 85-3934 administration in male Wistar rats treated with gentamicin to induce renal anemia.Data are presented as means ± SEM. (A) Plasma EPO levels, and (B) kidney and (C) liver relative expression of erythropoietin (EPO) mRNA 4 h after oral administration of BAY 85-3934. Before administration, rats had been treated with vehicle or gentamicin. (n = 5 animals per group). *p<0.05, **p<0.01, and ***p<0.001 compared with vehicle group, §p<0.05 and §§p<0.001 compared with control group, t-test. (D) Kidney and (E) liver mRNA expression levels of hypoxia-inducible factor target genes relative to mean of vehicle treated animals after oral administration of BAY 85-3934 (n = 4 to 5 animals per group, error bars not shown for clarity of presentation). For definition of gene symbols, see Table 1. (F) Time-course of changes in packed cell volume (PCV) following treatment with BAY 85-3934 or vehicle (once daily, five times per week, number of animals as indicated). (G) Hemoglobin levels 7 days after start of treatment with BAY 85-3934 or vehicle at day 22 of experiment shown in (F). *p<0.05, **p<0.01, and ***p<0.001 compared with vehicle group; #p<0.05 compared with sham group; t-test.
Mentions: The effect of BAY 85-3934 on the induction of endogenous EPO production was evaluated in an animal model of impaired kidney function, the gentamicin-induced kidney failure model. A mean creatinine clearance of 30% of that of untreated animals and high expression levels of several markers of acute and chronic kidney injury were indicative of substantial renal impairment in these animals. Treatment with BAY 85-3934 significantly and dose-dependently induced plasma EPO levels (Fig. 4A). Accordingly, EPO mRNA expression increased dose-dependently in kidney samples taken from these animals (Fig. 4B). The mean absolute levels of induction were lower in the gentamicin-treated animals than in the controls.

Bottom Line: Mimicking hypoxia by inhibiting HIF-PHs, thereby stabilizing HIF, is a novel treatment concept for restoring endogenous EPO production.Notably, unlike treatment with the antihypertensive enalapril, the blood pressure normalization was achieved without a compensatory activation of the renin-angiotensin system.Clinical studies are ongoing to investigate the effects of BAY 85-3934 therapy in patients with renal anemia.

View Article: PubMed Central - PubMed

Affiliation: Cardiology/Hematology, Acute Care Research, Global Drug Discovery, Bayer Pharma AG, Wuppertal, Germany.

ABSTRACT
Oxygen sensing by hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) is the dominant regulatory mechanism of erythropoietin (EPO) expression. In chronic kidney disease (CKD), impaired EPO expression causes anemia, which can be treated by supplementation with recombinant human EPO (rhEPO). However, treatment can result in rhEPO levels greatly exceeding the normal physiological range for endogenous EPO, and there is evidence that this contributes to hypertension in patients with CKD. Mimicking hypoxia by inhibiting HIF-PHs, thereby stabilizing HIF, is a novel treatment concept for restoring endogenous EPO production. HIF stabilization by oral administration of the HIF-PH inhibitor BAY 85-3934 (molidustat) resulted in dose-dependent production of EPO in healthy Wistar rats and cynomolgus monkeys. In repeat oral dosing of BAY 85-3934, hemoglobin levels were increased compared with animals that received vehicle, while endogenous EPO remained within the normal physiological range. BAY 85-3934 therapy was also effective in the treatment of renal anemia in rats with impaired kidney function and, unlike treatment with rhEPO, resulted in normalization of hypertensive blood pressure in a rat model of CKD. Notably, unlike treatment with the antihypertensive enalapril, the blood pressure normalization was achieved without a compensatory activation of the renin-angiotensin system. Thus, BAY 85-3934 may provide an approach to the treatment of anemia in patients with CKD, without the increased risk of adverse cardiovascular effects seen for patients treated with rhEPO. Clinical studies are ongoing to investigate the effects of BAY 85-3934 therapy in patients with renal anemia.

Show MeSH
Related in: MedlinePlus