Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes

Abstract

f Erythropoietin (Epo) is produced in the kidney and liver in a hypoxia-inducible manner via the activation of hypoxia-inducible transcription factors (HIFs) to maintain oxygen homeostasis. Accelerating Epo production in hepatocytes is one plausible therapeutic strategy for treating anemia caused by kidney diseases. To elucidate the regulatory mechanisms of hepatic Epo production, we analyzed mouse lines harboring liver-specific deletions of genes encoding HIF-prolyl-hydroxylase isoforms (PHD1, PHD2, and PHD3) that mediate the inactivation of HIF1␣ and HIF2␣ under normal oxygen conditions. The loss of all PHD isoforms results in both polycythemia, which is caused by Epo overproduction, and fatty livers. We found that deleting any combination of two PHD isoforms induces polycythemia without steatosis complications, whereas the deletion of a single isoform induces no apparent phenotype. Polycythemia is prevented by the loss of either HIF2␣ or the hepatocyte-specific Epo gene enhancer (EpoHE). Chromatin analyses show that the histones around EpoHE dissociate from the nucleosome structure after HIF2␣ activation. HIF2␣ also induces the expression of HIF3␣, which is involved in the attenuation of Epo production. These results demonstrate that the total amount of PHD activity is more important than the specific function of each isoform for hepatic Epo expression regulated by a PHD-HIF2␣-EpoHE cascade in vivo.

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.…”

Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients

“…The specialized REPs do not respond to the developing anemia with EPO production. In CKD, the pattern of EPO expression reflects these changes, moving from a pattern of renal predominance to hepatic predominance [48]. …”

Erythropoietin between therapy and doping : Two sides of the same coin

“…Some studies suggest possible role of proximal tubular cells in EPO production (5). In liver, EPO producing cells are hepatocytes and perisinusoidal (Ito) cells (1,6). Synthesis of EPO is hypoxia dependent, and physiological hypoxia appears during high altitude exposure, or strenuous exercise.…”

“…Synthesis of EPO is hypoxia dependent, and physiological hypoxia appears during high altitude exposure, or strenuous exercise. Important role here play hypoxia inducible factors 1 and 2 (HIF 1 and 2) which induce erythropoietin gene transcription (1,6). These are ubiquitary enzymes, but HIF 2 is more present in kidney and liver cells, and hence more specific for EPO gene transcription (7,8).…”