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Reactivation of hepatic EPO synthesis in mice after PHD loss - PubMed

️Fri Jan 01 2010

Reactivation of hepatic EPO synthesis in mice after PHD loss

Yoji Andrew Minamishima et al. Science. 2010.

Abstract

The kidney controls erythropoietin production in adults, and the anemia that can accompany renal failure is a major medical problem. The liver controls erythropoietin production during fetal life but is silenced shortly after birth. Erythropoietin transcription is controlled by hypoxia-inducible factor (HIF), which is inhibited by three prolyl hydroxylases (PHD1, PHD2, and PHD3). Systemic PHD2 inactivation has been found to increase renal, but not hepatic, erythropoietin production. In contrast, we show here that simultaneous genetic inactivation of all three PHD paralogs in mice reactivates hepatic erythropoietin production and stimulates red blood synthesis, suggesting that pan-PHD inhibitory drugs might be useful for the treatment of anemia caused by chronic kidney disease.

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Figures

**Fig. 1**
Hepatic EPO synthesis. (A) Real-time reverse transcription polymerase chain reaction (RT-PCR) analysis of hepatic *Epo* mRNA (solid bars) and serum Epo concentrations (open bars) in 4-week-old male mice with indicated genotypes. n = 3 mice per group. Pound symbols indicate P < 0.0001 comparing indicated genotype versus wild type (wt). DKO, double knockout; TKO, triple knockout. Note that *Phd2* KO and *Vhl* KO are liver-specific. Error bars indicate 1 SEM. (B) Immunoblots of livers from 4-week-old mice as in (A). Mean hematocrits (Hct) are also shown. (C) Real-time RT-PCR analysis of hepatic *Epo* mRNA from 4-week-old mice with indicated genotypes 1 week after tamoxifen treatment. n = 3. **P < 0.01. Error bars indicate 1 SEM.

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Reactivation of hepatic EPO synthesis in mice after PHD loss - PubMed