Treatment of erythropoietin deficiency in mice with systemically administered siRNA

Abstract

Anemia linked to a relative deficiency of renal erythropoietin production is a significant cause of morbidity and medical expenditures in the developed world. Recombinant erythropoietin is expensive and has been linked to excess cardiovascular events. Moreover, some patients become refractory to erythropoietin because of increased production of factors such as hepcidin. During fetal life, the liver, rather than the kidney, is the major source of erythropoietin. In the present study, we show that it is feasible to reactivate hepatic erythropoietin production and suppress hepcidin levels using systemically delivered siRNAs targeting the EglN prolyl hydroxylases specifically in the liver, leading to improved RBC production in models of anemia caused by either renal insufficiency or chronic inflammation with enhanced hepcidin production. (Blood. 2012;120(9): [1916][1917][1918][1919][1920][1921][1922]

Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin

“…Inactivation of all 3 PHDs is required for a strong and sustained EPO production in the liver (19)(20)(21)(22)(23) ) did not change rbc parameters or induce renal Epo transcription (Supplemental Figure 3). In contrast, Foxd1-Phd2 -/-mutants developed polycythemia.…”

“…While our study identified at least 2 interstitial cell populations in the kidney that displayed differential sensitivity to Phd2 inactivation, inactivation of at least 2 HIF-PHDs is required for moderate Epo induction in hepatocytes. To achieve very high levels of Epo induction in the liver, inactivation of all 3 HIF-PHDs is required (21)(22)(23). The role of individual PHDs in the regulation of EPO in other cell types, however, is not clear.…”

Patients with anaemia can shift from kidney to liver production of erythropoietin as shown by glycoform analysis

“…Pharmacological manipulation of the hypoxia-inducible transcription factor (HIF) has been shown to stimulate endogenous EPO production [7]. Methods for up-regulating production of EPO from the liver seem especially attractive as an alternative to therapy with rhEPO when kidney production has ceased [8].…”

Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes

“…However, the level of hepatic Epo production is weak and insufficient to compensate for renal anemia (13). Therefore, pharmacological enhancement of hepatic Epo production is a reasonable strategy for treating anemic patients who have renal diseases (14,15).…”