Multiple consequences of HIF activation in CKD

Abstract

Tubulointerstitial hypoxia negatively influences the balance between injury and repair, and serves as a final common pathway in chronic kidney disease (CKD). Studies on erythropoietin (EPO) transcription led to the identification of hypoxia inducible factors (HIFs) and their key regulators, prolyl hydroxylases (PHDs). Based on these, several small molecule PHD inhibitors are developed for the treatment of anemia in CKD, which are currently in phase II/III clinical trials. In addition to treating anemia, application of PHD inhibitors may have several potential implications; there is a promising view that activation of the HIF signaling might protect the ischemic kidney from injury. This is extensively tested in multiple acute kidney injury models, whereas knowledge is limited in the context of CKD. Some studies demonstrate the protective effects of ameliorating inflammation and reducing oxidative stress, whereas negative consequences of sustained HIF activation, such as renal fibrosis and aggravation of polycystic kidney disease, are also reported. Recent human clinical studies reported amelioration in glucose and lipid metabolism, which may be beneficial for the treatment of metabolic kidney disorders. Renal consequences of PHD inhibitors are likely determined by multiple systemic effects of sustained HIF activation and may thus differ depending on the clinical context and the pathological stages.