Potential Application of HIF-PH Inhibitors to Treat Kidney Diseases

Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors have recently been approved for clinical use in the treatment of renal anemia. HIF-PH inhibitors were developed following studies investigating the role of HIFs and their molecular mechanisms. Unlike erythropoiesis-stimulating agents, these orally administered agents improve renal anemia in patients with chronic kidney disease (CKD) and chronic inflammation. HIF-PH inhibitors improve renal anemia by stabilizing HIF-2α, which increases erythropoietin production. They also improve iron metabolism by suppressing hepcidin and inducing the expression of iron transport-related genes. The renoprotective effects of HIF-PH inhibitors are controversial, owing to the opposing effects of hypoxia-inducible factor 1-alpha (HIF-1α) and hypoxia-inducible factor 2-alpha (HIF-2α) on kidney injury. They induce the expression of both HIF-1α and HIF-2α. HIF-2α plays a key role in erythropoietin production and mitigates CKD. Although HIF-1α contributes to cell survival under hypoxic conditions, its overexpression is suspected to exacerbate kidney injury in CKD. This review summarizes the development of HIF and HIF-PH, from their discovery to the elucidation of their regulatory mechanisms and the development of HIF-PH inhibitors. We reviewed basic research and recently published clinical studies investigating the effects of HIF-PH inhibitors on renal injury, focusing on their clinical use in treating renal injury rather than renal anemia. We discuss the possible benefits of HIF-PH inhibitors used clinically for acute and chronic kidney injury, especially in the advanced stages of CKD.