Regulation of Erythropoiesis by the Hypoxia-Inducible Factor Pathway: Effects of Genetic and Pharmacological Perturbations

Red blood cells transport O binf 2 einf from the lungs to body tissues. Hypoxia stimulates kidney cells to secrete erythropoietin (EPO), which increases red cell mass. Hypoxia-inducible factors (HIFs) mediate EPO gene transcriptional activation. HIF- alpha subunits are subject to O binf 2 einf -dependent prolyl hydroxylation and then bound by the von Hippel-Lindau protein (VHL), which triggers their ubiquitination and proteasomal degradation. Mutations in the genes encoding EPO, EPO receptor, HIF-2 alpha , prolyl hydroxylase domain protein 2 (PHD2), or VHL cause familial erythrocytosis. In addition to O binf 2 einf , alpha -ketoglutarate is a substrate for PHD2, and analogs of alpha -ketoglutarate inhibit hydroxylase activity. In phase III clinical trials evaluating the treatment of anemia in chronic kidney disease, HIF prolyl hydroxylase inhibitors were as efficacious as darbepoetin alfa in stimulating erythropoiesis. However, safety concerns have arisen that are focused on thromboembolism, which is also a phenotypic manifestation of VHL or HIF-2 alpha mutation, suggesting that these events are on-Target effects of HIF prolyl hydroxylase inhibitors.