Nephrology

Pathophysiology of Diabetic Kidney Disease (DKD) is complex. In addition to high glucose-induced inflammation, oxidative stress and activation of the renin-angiotensin system, the pathogenic role of chronic hypoxia in the tubulointerstitium is increasingly recognized. Beginning from the early stage of DKD, an increase in oxygen consumption secondary to mitochondrial uncoupling reduces local oxygenation, and together with loss of peritubular capillaries and impaired oxygen diffusion, negatively influences the balance of injury and repair in tubular epithelial cells and serves as a final common pathway leading to fibrosis. Studies on Erythropoietin (EPO) transcription led to the identification of Hypoxia Inducible Factors (HIFs) and their key regulators, Prolyl Hydroxylases (PHDs). Inhibition of Ph.D. leads to HIF stabilization irrespective of oxygen content and up-regulates EPO, as well as other 100-200 target genes involved in processes such as angiogenesis and anaerobic metabolism necessary for cellular hypoxic adaptation. Based on this, several small molecule PHD inhibitors are currently under human clinical trials for the treatment of anemia in CKD. Application of PHD inhibitors has several potential implications beyond anemia treatment. Because HIF drives the expression of genes essential to adaptation to hypoxia, there is a promising view that activation of HIF using PHD inhibitors might protect against DKD. Besides, animal and human clinical studies even suggest that PHD inhibitors may improve glucose and lipid metabolism, which may also orchestrate protection against DKD progression.