Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes.

Journal Article (Journal Article)

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 HIF1α and HIF2α 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 HIF2α or the hepatocyte-specific Epo gene enhancer (EpoHE). Chromatin analyses show that the histones around EpoHE dissociate from the nucleosome structure after HIF2α activation. HIF2α also induces the expression of HIF3α, 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-HIF2α-EpoHE cascade in vivo.

Full Text

Duke Authors

Cited Authors

  • Tojo, Y; Sekine, H; Hirano, I; Pan, X; Souma, T; Tsujita, T; Kawaguchi, S-I; Takeda, N; Takeda, K; Fong, G-H; Dan, T; Ichinose, M; Miyata, T; Yamamoto, M; Suzuki, N

Published Date

  • August 2015

Published In

Volume / Issue

  • 35 / 15

Start / End Page

  • 2658 - 2672

PubMed ID

  • 26012551

Pubmed Central ID

  • PMC4524113

Electronic International Standard Serial Number (EISSN)

  • 1098-5549

Digital Object Identifier (DOI)

  • 10.1128/MCB.00161-15


  • eng

Conference Location

  • United States