Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis

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.

HIF2α regulates the synthesis and release of epinephrine in the adrenal medulla

“…Therefore, further insight into how PHDs/HIFs regulate epinephrine production and release from the adrenal medulla in an in vivo setting is essential to further implement this knowledge in the promising field of HIF stabilizers (HIF-PHD inhibitors) in the treatment of anemia. However, it must be noted here that concerns have been recently raised regarding the chronic use of such HIF stabilizers [3,[50][51][52][53].…”

“…Reduced cellular oxygen levels preclude such hydroxylation of HIFs by PHDs, resulting in stabilization of HIFα and direct transcriptional activation of more than 1000 genes. HIF transcriptional targets are primarily involved in a wide range of biological processes that serve to reverse the unfavorable hypoxic state, including erythropoiesis, blood pressure regulation, and adrenocortical hormone production [2][3][4]. Hypoxia is also a central feature of multiple pathologies, including local and systemic inflammation, and various stages of tumorigenesis or metastatic progression; gene mutations that impact hypoxia signaling are particularly important for development of pheochromocytomas, tumors originating from the adrenal chromaffin cells [5].…”

Erythropoietin (EPO) as a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial Transdifferentiation of Multipotent Mesenchymal Stem Cells (MSCs): Implications in Regenerative Medicine

“…An increase in the EPO end product then leads to a feedback loop inhibition of the HIF1α transactivation via blockade of interactions with co-activator proteins. Briefly, the hypoxia pathway proteins are master regulators of erythropoiesis [19]. The discovery of the hypoxia-inducing factor (HIF) as the major transactivator of the EPO gene expression mechanistically explained the regulation of EPO synthesis and paved the groundwork for the award of the Nobel prize in Physiology or Medicine to William G. Kaelin, Jr., Sir Peter John Ratcliffe and Gregg L. Semenza in 2019 [20].…”

Znaczenie hipoksji w nowotworach głowy i szyi

“…Hormon ten wydzielany jest endokrynowo i wiąże się z receptorami na powierzchni niedojrzałych erytrocytów wpływając na ich różnicowanie i proliferację [15]. Dodatkowo HIF wpływa na syntezę hemoglobiny poprzez działanie stymulujące na geny związane z metabolizmem żelaza, w tym: transferryny (Tf ), receptora dla transferryny (Tfr-1) [16] oraz na transkrypcję genu receptora EPO (epo-r). W skutek tych procesów dochodzi do wytwarzania czerwonych krwinek i tym samym zapobiegania skutkom hipoksji w tkance nowotworowej.…”

“…Receptor dla erytropoetyny [17] c-myc Protoonkogen, kodujący czynnik transkrypcyjny c-Myc [20] onkostatyna M Cytokina należąca do rodziny IL-6 [21] Tf Transferryna, białko transportujące żelazo [16] Tfr-1 Receptor dla transferryny [16] Wykazano, że w materiałach z biopsji nowotworów jamy ustnej, gardła i krtani stężenie EPO i EPO-R jest znacznie zwiększone w porównaniu do zdrowych tkanek [19]. Inne badanie pokazało, że podawanie rekombinowanej erytropoetyny w celu leczenia anemii, będącej skutkiem radioterapii, może niekorzystnie wpływać na rokowanie pacjentów z nowotworami głowy i szyi, jeżeli komórki rakowe wykazują ekspresję EPO-R [22].…”