Simvastatin downregulates the expression of hepcidin and erythropoietin in HepG2 cells

Abstract

Statin therapy may improve responsiveness to erythropoietin-stimulating agents in patients with end-stage renal disease. Although statins increase hepatic iron uptake and storage capacity in cholestatic rats, the underlying mechanisms are unclear. Therefore, we examined the effects of a statin (simvastatin) on the expression of hepcidin, erythropoietin receptor (EPOR) and erythropoietin (EPO) in cultured HepG2 cells. HepG2 cells (6-6.5 × 10(5) cells) were seeded in 6-cm dishes and incubated overnight. The cells were then treated with 0, 0.5, 1, 3, 5, or 10 μM simvastatin, and the mRNA expression of hepcidin, EPOR, and EPO was determined. Data were collected from three independent experiments. The cDNA extracted from the cells was used as a template for real-time polymerase chain reaction, and each sample was tested in duplicate. Significant differences (P < 0.05) among groups were determined using one-way analysis of variance with Fisher's least significant difference post hoc test. Data were adjusted using Bonferroni's method. The relative mRNA expression of hepcidin in HepG2 cells treated with 0.5, 1, 3, 5, and 10 μM simvastatin, relative to the control group, was 0.7273, 0.3303, 0.2418, 0.4131, and 0.4064, respectively. The relative mRNA expression of EPOR was 0.5196, 0.2319, 0.2398, 0.4253, and 0.1245, respectively, while that of EPO was 0.9751, 0.4712, 0.4613, 0.4875, and 0.1654. There was a reverse dose-dependent effect of simvastatin. These results suggest that statins increase erythropoiesis by targeting hepcidin and iron regulatory pathways, independent of erythropoietin.

Higher androgen bioactivity is associated with excessive erythrocytosis and chronic mountain sickness in Andean Highlanders: a review

“…This suggests that testosterone reducing hepcidin levels may increase iron bioavailability and stimulate erythropoietic activity. In addition, compounds that can modify hepcidin levels may affect erythropoiesis independent of erythropoietin action (Chang et al ., ).…”

Serum testosterone levels and excessive erythrocytosis during the process of adaptation to high altitudes

“…This effect could also occur without affecting the serum EPO levels, based on recent findings suggesting that administration of statins may increase erythropoiesis by targeting the hepcidin and iron regulatory pathways independent of erythropoietin. 89 …”

Iron and Atherosclerosis: Nailing Down a Novel Target with Magnetic Resonance

“…In particular, statin therapy appears to downregulate hepcidin, leading to decreased degradation of ferroportin and increased efflux of iron from macrophages [98]. Zacharski et al , whose randomized trial of iron reduction via phlebotomy in patients with established peripheral arterial disease showed variable impact on outcomes in all patients[99], recently published secondary outcome results focused on statin therapy [100].…”