Mimicking Hypoxia to Treat Anemia: HIF-Stabilizer BAY 85-3934 (Molidustat) Stimulates Erythropoietin Production without Hypertensive Effects
Figure 2
Characterization of the in vivo activity of BAY 85-3934 (in male Wistar rats).
Data are presented as means ± SEM. (A) Increase in plasma erythropoietin (EPO) at 4 h and (B) reticulocytes (as a proportion of red blood cells [RBCs]) at 72 h following single oral dosing of BAY 85-3934. Data were pooled from two sequential experiments (n = 2×5 animals per group). *p<0.05, **p<0.01, and ***p<0.001; unpaired t-test, sequentially pairwise-applied to dose groups and corresponding vehicle group. (C) Change in packed cell volume (PCV) during once-daily dosing with BAY 85-3934 (n = 12 animals per group). **p<0.01 and ***p<0.001; two-way ANOVA with Dunnett’s multiple comparison test versus vehicle group. (D) Induction of erythropoiesis after subcutaneous administration of recombinant human EPO (rhEPO) twice weekly or BAY 85-3934 (2.5 mg/kg) once daily (n = 10 animals per group). *p<0.001 compared with control (t-test) at day 30. (E) BAY 85-3934 plasma levels, kidney EPO relative mRNA expression, and plasma EPO levels after oral administration of BAY 85-3934 (5 mg/kg) (n = 5 animals per group). (F) Relative mRNA expression levels of HIF target genes in rat kidney after administration of BAY 85-3934 (5 mg/kg). Baseline expression was set at 1 (n = 5 animals per group; error bars not show for clarity of presentation). For definition of gene symbols, see Table 1.