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

Annu Rev Med. 2022 Jun 30. doi: 10.1146/annurev-med-042921-102602. Online ahead of print.ABSTRACTRed blood cells transport O2 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-α subunits are subject to O2-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-2α, prolyl hydroxylase domain protein 2 (PHD2), or VHL cause familial erythrocytosis. In addition to O2, α-ketoglutarate is a substrate for PHD2, and analogs of α-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-2α mutation, suggesting that these events are on-target effects of HIF prolyl hydroxylase inhibitors. Expected final online publication date for the Annual Review of Medicine, Volume 74 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.PMID:35773226 | DOI:10.1146/annurev-med-042921-102602
Source: Annual Review of Medicine - Category: General Medicine Authors: Source Type: research