Multiple consequences of HIF activation in CKD

Abstract

In chronic kidney disease (CKD), tubulointerstitial hypoxia is regarded as a final common pathway leading to end-stage kidney disease. Insufficient oxygenation negatively influences the balance between injury and repair in tubular epithelial cells.

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. Studies so far demonstrate successful increases in hemoglobin levels by raising plasma EPO levels and optimizing iron utilization.

Application of PHD inhibitors has several potential implications beyond anemia treatment, and there is a promising view that activation of the HIF signaling might protect the ischemic kidney from injury. This concept is extensively tested in multiple acute kidney injury models, but knowledge is limited in the context of CKD. Some studies demonstrate the protective effects of ameliorating inflammation and reducing oxidative stress. In human clinical studies, some of the PHD inhibitors exhibit the additional advantage in terms of glucose and lipid metabolism, which may be beneficial for the treatment of metabolic kidney disorders. On the other hand, negative consequences of sustained HIF activation are also reported, including renal fibrosis and aggravation of polycystic kidney disease. Renal consequences are likely determined by multiple systemic effects of PHD inhibition and may thus differ depending on the clinical context and the pathological stages.