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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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Effect of BAY 85-3934 administration on peptidoglycan-polysaccharide (PG-PS)-induced inflammatory anemia in female Lewis rats.Data are presented as means ± SEM. (A) Packed cell volume (PCV) in PG-PS-treated animals administered BAY 85-3934 or vehicle (n = 11–12 animals per group), compared with control animals treated with vehicle alone (n = 5 animals). (B) Relative expression of erythropoietin (EPO) and monocyte chemotactic protein-1 (MCP-1) mRNA in kidney, and hepcidin mRNA in liver at the end of the study. *p<0.05, **p<0.01, and ***p<0.001; t-test.
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pone-0111838-g005: Effect of BAY 85-3934 administration on peptidoglycan-polysaccharide (PG-PS)-induced inflammatory anemia in female Lewis rats.Data are presented as means ± SEM. (A) Packed cell volume (PCV) in PG-PS-treated animals administered BAY 85-3934 or vehicle (n = 11–12 animals per group), compared with control animals treated with vehicle alone (n = 5 animals). (B) Relative expression of erythropoietin (EPO) and monocyte chemotactic protein-1 (MCP-1) mRNA in kidney, and hepcidin mRNA in liver at the end of the study. *p<0.05, **p<0.01, and ***p<0.001; t-test.

Mentions: Daily treatment of rats with BAY 85-3934 (5 mg/kg) reversed mean PCV decline, and values returned to normal levels within 5 weeks of PG-PS challenge (Fig. 5A). The low dose of BAY 85-3934, 2.5 mg/kg, halted further decline of mean PCV levels, and by the end of the study, there was a trend for mean PCV values to be higher than in PG-PS-pretreated animals that received vehicle only. A small but significant increase in kidney EPO mRNA expression, interpreted as anemia-reactive, was not sufficient to counteract the inflammation-induced anemia in PG-PS-challenged animals. However, in response to treatment with BAY 85-3934, a significantly larger increase in EPO mRNA expression in the kidneys was observed. Among the inflammatory markers, the expression levels of monocyte chemotactic protein-1 and hepcidin were significantly reduced in animals in the 5 mg/kg dose group (Fig. 5B). Although treatment did not influence the course of polyarthritis, as monitored by hind limb ankle diameter and development of body weight gain, the initial increase in white blood cell count was attenuated (data not shown).


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)

Effect of BAY 85-3934 administration on peptidoglycan-polysaccharide (PG-PS)-induced inflammatory anemia in female Lewis rats.Data are presented as means ± SEM. (A) Packed cell volume (PCV) in PG-PS-treated animals administered BAY 85-3934 or vehicle (n = 11–12 animals per group), compared with control animals treated with vehicle alone (n = 5 animals). (B) Relative expression of erythropoietin (EPO) and monocyte chemotactic protein-1 (MCP-1) mRNA in kidney, and hepcidin mRNA in liver at the end of the study. *p<0.05, **p<0.01, and ***p<0.001; t-test.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111838-g005: Effect of BAY 85-3934 administration on peptidoglycan-polysaccharide (PG-PS)-induced inflammatory anemia in female Lewis rats.Data are presented as means ± SEM. (A) Packed cell volume (PCV) in PG-PS-treated animals administered BAY 85-3934 or vehicle (n = 11–12 animals per group), compared with control animals treated with vehicle alone (n = 5 animals). (B) Relative expression of erythropoietin (EPO) and monocyte chemotactic protein-1 (MCP-1) mRNA in kidney, and hepcidin mRNA in liver at the end of the study. *p<0.05, **p<0.01, and ***p<0.001; t-test.
Mentions: Daily treatment of rats with BAY 85-3934 (5 mg/kg) reversed mean PCV decline, and values returned to normal levels within 5 weeks of PG-PS challenge (Fig. 5A). The low dose of BAY 85-3934, 2.5 mg/kg, halted further decline of mean PCV levels, and by the end of the study, there was a trend for mean PCV values to be higher than in PG-PS-pretreated animals that received vehicle only. A small but significant increase in kidney EPO mRNA expression, interpreted as anemia-reactive, was not sufficient to counteract the inflammation-induced anemia in PG-PS-challenged animals. However, in response to treatment with BAY 85-3934, a significantly larger increase in EPO mRNA expression in the kidneys was observed. Among the inflammatory markers, the expression levels of monocyte chemotactic protein-1 and hepcidin were significantly reduced in animals in the 5 mg/kg dose group (Fig. 5B). Although treatment did not influence the course of polyarthritis, as monitored by hind limb ankle diameter and development of body weight gain, the initial increase in white blood cell count was attenuated (data not shown).

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