biostudies-literatureGhosh MCEunice Kennedy Shriver NICHD Intramural Research ProgramEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health1317-1325https://www.ebi.ac.uk/biostudies/studies/S-EPMC5873849biostudies-literatureUnknown128(4)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. WThe Journal of clinical investigationTranslational repression of HIF2α expression in mice with Chuvash polycythemia reverses polycythemia.PMC5873849Eunice Kennedy Shriver NICHD Intramural Research ProgramN/AEckhaus MAZhang DLGhosh MCOllivierre HRouault TAfalseTranslational repression of HIF2α expression in mice with Chuvash polycythemia reverses polycythemia.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. W2018-01-01T00:00:00Z2018 Apr2025-04-26T03:38:00.037Z2019-03-26T23:44:13ZS-EPMC58738492948082010.1172/jci9768410.1172/JCI97684