Prolyl hydroxylase domain inhibitors as a novel therapeutic approach against anemia in chronic kidney disease

Anemia is a common complication of chronic kidney disease and is mainly caused by the inability of injured kidneys to produce adequate amounts of erythropoietin. Studies elucidating the regulation of erythropoietin production led to the identification of hypoxia-inducible factor (HIF), which activates the transcription of genes that mediate adaptive responses to hypoxia. HIF is a heterodimer that consists of an alpha and beta subunit. While HIF-beta is constitutively expressed, HIF-alpha is subjected to ubiquitination and proteasomal degradation under normoxic conditions. This process is mediated by prolyl hydroxylase domain proteins, the inhibition of which results in an increased expression of hypoxia-induced genes, including erythropoietin. These findings led to the development of prolyl hydroxylase domain inhibitors as novel therapeutic agents against anemia in chronic kidney disease. Prolyl hydroxylase domain inhibition improves iron metabolism, which also contributes to erythropoiesis. To date, at least 6 small-molecule inhibitors of the prolyl hydroxylase domain have been tested in humans, and clinical trials have shown that they are effective without causing serious adverse events. However, there is a theoretical concern that the systemic activation of HIF could also induce deleterious effects such as tumorigenesis and severe pulmonary hypertension, which demands careful assessments in future clinical studies.