The journey from erythropoietin to 2019 Nobel Prize: Focus on hypoxia-inducible factors in the kidney

The 2019 Nobel Prize in Physiology or Medicine was awarded to William G. Kaelin Jr, Sir Peter J. Ratcliffe, and Gregg L. Semenza “for their discoveries of how cells sense and adapt to oxygen availability.” The three pioneers discovered the hypoxia-inducible factor (HIF), elucidated the oxygen sensing mechanism of cells, and confirmed the critical role of HIF in hypoxic cellular responses. The broad and profound biological effects of HIF open up the possibilities for clinical translation. HIF stabilizers have been proven effective on anemia of chronic kidney disease in phase III clinical trials. HIF antagonists for cancer treatment are under phase II clinical trials. It is imperative to gain insight into the biology of HIF. In this article, the discovery of HIF and its oxygen-dependent enzymatic regulation will be introduced, based largely on the groundbreaking work of the three Nobel laureates. Next, the biology of HIF in the kidney will be reviewed. Studies on the HIF stabilizers in the context of kidney disease, as well as the manipulation of HIF in different renal cell types will be covered. Lastly, the clinical application of HIF stabilizers and HIF antagonists for the treatment of anemia and cancer, respectively, will be discussed.