Translational repression of HIF2α expression in mice with Chuvash polycythemia reverses polycythemia

The Journal of Clinical Investigation
Manik C GhoshTracey A Rouault

Abstract

Chuvash polycythemia is an inherited disease caused by a homozygous germline VHLR200W mutation, which leads to impaired degradation of HIF2α, elevated levels of serum erythropoietin, and erythrocytosis/polycythemia. This phenotype is recapitulated by a mouse model bearing a homozygous VhlR200W mutation. We previously showed that iron-regulatory protein 1-knockout (Irp1-knockout) mice developed erythrocytosis/polycythemia through translational derepression of Hif2α, suggesting that IRP1 could be a therapeutic target to treat Chuvash polycythemia. Here, we fed VhlR200W mice supplemented with Tempol, a small, stable nitroxide molecule and observed that Tempol decreased erythropoietin production, corrected splenomegaly, normalized hematocrit levels, and increased the lifespans of these mice. We attribute the reversal of erythrocytosis/polycythemia to translational repression of Hif2α expression by Tempol-mediated increases in the IRE-binding activity of Irp1, as reversal of polycythemia was abrogated in VhlR200W mice in which Irp1 was genetically ablated. Thus, a new approach to the treatment of patients with Chuvash polycythemia may include dietary supplementation of Tempol, which decreased Hif2α expression and markedly reduced li...Continue Reading

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Citations

Oct 24, 2018·The Journal of Clinical Investigation·Andrew J SchwartzYatrik M Shah
Mar 12, 2019·Current Opinion in Hematology·Cyril Renassia, Carole Peyssonnaux
Aug 15, 2020·Antioxidants & Redox Signaling·Tiago L DuarteHal Drakesmith
Sep 7, 2019·Nature Reviews. Nephrology·Johannes Schödel, Peter J Ratcliffe
Jan 8, 2019·The Journal of Clinical Investigation·John C ChappellW Kimryn Rathmell
Mar 30, 2019·Biometals : an International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine·Tracey A Rouault
Jul 27, 2018·HemaSphere·Francesca Vinchi
Aug 21, 2020·Learning & Memory·Jack T Rogers, Catherine M Cahill
Oct 2, 2021·Proceedings of the National Academy of Sciences of the United States of America·Jin-Seon YookSoonkyu Chung

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Methods Mentioned

BETA
ELISA
RNA

Software Mentioned

GraphPad
GraphPad Prism
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