Abstract
Erythropoiesis is a complex process driving the production of red blood cells. During homeostasis, adult erythropoiesis takes place in the bone marrow and is tightly controlled by erythropoietin (EPO), a central hormone mainly produced in renal EPO-producing cells. The expression of EPO is strictly regulated by local changes in oxygen partial pressure (pO2) as under-deprived oxygen (hypoxia); the transcription factor hypoxia-inducible factor-2 induces EPO. However, erythropoiesis regulation extends beyond the well-established hypoxia-inducible factor (HIF)–EPO axis and involves processes modulated by other hypoxia pathway proteins (HPPs), including proteins involved in iron metabolism. The importance of a number of these factors is evident as their altered expression has been associated with various anemia-related disorders, including chronic kidney disease. Eventually, our emerging understanding of HPPs and their regulatory feedback will be instrumental in developing specific therapies for anemic patients and beyond.
Highlights
Red blood cell (RBC) production mainly takes place in the bone marrow during homeostasis
hypoxia-inducible factor (HIF) stabilizers act by restoring EPO levels and reducing hepcidin and have been used effectively to enhance hemoglobin levels in patients suffering from anemias, including chronic kidney disease (CKD) patients [149]
We recently showed that increased fibroblast growth factor-23 (FGF-23) levels are associated with ineffective erythropoiesis and impaired bone mineralization in myelodysplastic syndromes (MDS) [159]
Summary
Red blood cell (RBC) production mainly takes place in the bone marrow during homeostasis This process encompasses a number of proliferation and differentiation steps, starting at the hematopoietic stem cell (HSC) and down to specialized erythroid progenitors, turning into mature RBCs. The complex process of erythropoiesis is vastly intertwined with iron metabolism [1] and regulated by a number of cytokines, including the central glycoprotein hormone erythropoietin (EPO). A limited amount of enzymes, three HIF prolyl hydroxylase domain proteins (PHD1–3), and factor-inhibiting HIF (FIH) have been identified as oxygen sensors These oxygen-dependent enzymes act as hydroxylases and dioxygenases, regulating the availability of HIFα subunits, and, in turn, define when and how cells express genes in response to changing pO2 [10,11,12]. This review will give a more indepth view on the role of HPPs (i.e., HIFα, PHDs, HIF-controlled genes) regulating the multistage process of erythropoiesis and discusses the current therapeutic approaches interfering with the hypoxia pathway in the treatment of anemia and/or chronic kidney disease (CKD) [16]
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