HIF–Prolyl Hydroxylase Inhibitor Desidustat Increases Pyruvate Kinase Activity and Reduces Oxidative Stress in Red Blood Cells, Causes Erythrocytosis in Thalassaemic Mice, and Reduces Sickling in Sickle Cell Patient's Blood

Abstract

Sickle cell anemia and beta-thalassemia are the major hemoglobinopathies associated with anemia. Bone marrow transplants or blood transfusion are frequently employed as treatment for these diseases, and erythropoietin analogues are sometimes used to boost erythropoiesis to compensate the destruction of RBCs. RBCs of hemoglobinopathy patients have reduced pyruvate kinase activity and increased oxidative stress, which makes the RBCs prone to destruction and precipitate vaso-occlusive crises and pain. The objective of this study was to evaluate desidustat, a hypoxia inducible factor (HIF) stabilizer in beta thalassemic mice (B6.D2-Hbb^d3th/BrkJ) model, phenylhydrazine-induced acute hemolysis in C57 mice model, and sodium metabisulfite-induced sickling in sickle cell disease patient's blood. Desidustat treatment increased hemoglobin, RBCs, and hematocrit in both mice models. Desidustat treatment decreased iron overload, splenomegaly, and oxidative stress in phenylhydrazine-induced hemolytic anemia in mice. Desidustat treatment increased pyruvate kinase activity in RBCs of human, mice, and rats in a dose-dependent manner, and reduced sickling in SCD patients' RBCs. These data indicate that desidustat stimulates pyruvate kinase and attenuates oxidative stress in red blood cells, causes erythrocytosis in thalassemic mice, and reduces sickling in sickle cell patient's blood.