Abstract
Oxygen is essential for the maintenance of the body. Living organisms have evolved systems to secure an oxygen environment to be proper. Hypoxia-inducible factor (HIF) plays an essential role in this process; it is a transcription factor that mediates erythropoietin (EPO) induction at the transcriptional level under hypoxic environment. After successful cDNA cloning in 1995, a line of studies were conducted for elucidating the molecular mechanism of HIF activation in response to hypoxia. In 2001, cDNA cloning of dioxygenases acting on prolines and asparagine residues, which play essential roles in this process, was reported. HIF-prolyl hydroxylases (PHs) are molecules that constitute the core molecular mechanism of detecting a decrease in the partial pressure of oxygen, or hypoxia, in the cells; they can be called oxygen sensors. In this review, I discuss the process of molecular cloning of HIF and HIF-PH, which explains hypoxia-induced EPO expression; the development of HIF-PH inhibitors that artificially or exogenously activate HIF by inhibiting HIF-PH; and the significance and implications of medical intervention using HIF-PH inhibitors.
Highlights
FG-4497 administration to transplant donor rats improved the prognosis of transplanted grafts; upregulation of AgtPI4 and HO-1, inhibition of apoptosis, and activation of antioxidant pathways were observed in the renal tubular epithelium of the grafts [156]. These experimental results suggest that Hypoxia-inducible factor (HIF)-PHIs, when administered to renal transplant recipients or donors in advance, are promising nephroprotective agents against transient acute kidney injury (AKI) or renal ischemia-reperfusion injury that occurs after renal transplantation
HIF-prolyl hydroxylases (PHs) inhibitors cause a decrease in ferritin and an increase in TIBC after administration due to their complete effect on iron metabolism; administration of HIF-PHIs in iron-deficient patients may lead to iron deficiency, which reduces the effect of iron deficiency on anemia and causes iron deficiency symptoms in the bones, skin, and mucous membranes
On the basis of these findings, we investigated whether HIF-PHIs induce tumor vascular normalization and contribute to the improvement of the tumor tissue environment and found that administration of HIF-PHIs altered the vascular structure in tumor tissue [174]
Summary
Chronic kidney disease (CKD), cancers, inflammatory diseases, nutritional deficiencies, genetic disorders, and drugs may cause anemia. Hypoxia-inducible factor (HIF) plays an essential role in this process; it is a transcription factor that was genetically isolated while elucidating the molecular mechanism through which EPO is induced at the transcriptional level in hypoxia [11]. Pharmacological inhibition of HIF-PHs increases EPO and DMT1 (ferrous ion membrane transport protein 1)/Nramp (NRAMP metal ion transporter 2) in the intestinal epithelium and decreases hepcidin production in the liver, thereby improving iron metabolism in vivo and potentially leading to efficient treatment of CDK-induced anemia and anemia associated with chronic diseases [11,21,22,23]. I describe the process of molecular cloning of HIF and HIF-PH, which explains the induction of EPO expression by hypoxia; the development of HIF-PH inhibitors (HIF-PHIs) that artificially activate HIF by inhibiting HIF-PH; medical interventions that utilize HIF-PHIs; and the implications and significance of these interventions [24,25]. This review will describe HIF-PHIs, which are currently prescribed in medical practice, and explain its biological effects in addition to its anemia-alleviating effects in relation to its molecular mechanism
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