Oxygen is an essential molecule to produce energy. Sir Peter J. Ratcliffe ,Gregg L. Semenza, and William G. Kaelin Jr.,  got the Nobel prize in 2019 because they discovered how cells can sense and adapt to changing oxygen availability. Because of the characteristic vascular architecture and high energy demand to drive tubular solute transport, the kidney is susceptible and prone to hypoxia. Injured kidneys present capillary rarefaction, inflammation, and fibrosis, which contribute to sustained kidney hypoxia, forming a vicious cycle promoting progression of kidney disease. In addition, even transient hypoxia induces epigenetic changes to pose persistent effects. Thus, chronic hypoxia in the kidney is a final common pathway to end-stage kidney disease. Hypoxia-inducible factor (HIF), a transcription factor, is a master regulator of defensive mechanisms against hypoxia. HIF prolyl-hydroxylase (HIF-PH) regulates the expression level of HIF in an oxygen dependent manner. A representative target gene of HIF is erythropoietin, and now HIF-PH inhibitors are approved and available as a new treatment against anemia in CKD. In addition to induction of endogenous erythropoietin production, HIF activation will lead to increase expression of various iron transporters, resulting in efficient erythropoiesis. Theoretically HIF activation will protect the kidney, defending the kidney against chronic hypoxia. A number of experimental studies showed kidney protection by HIF activation, and the mechanisms of kidney protection include improvement of cellular metabolism. It remains to be determined whether HIF activation protects organs in human patients.   Yap DYH, McMahon LP, Hao CM, Hu N, Okada H, Suzuki Y, Kim SG, Lim SK, Vareesangthip K, Hung CC, Nangaku M; APSN HIF-PHI Recommendation Committee. Recommendations by the Asian Pacific society of nephrology (APSN) on the appropriate use of HIF-PH inhibitors. Nephrology (Carlton). 2021 Feb;26(2):105-118 Sugahara M, Tanaka S, Tanaka T, Saito H, Ishimoto Y, Wakashima T, Ueda M, Fukui K, Shimizu A, Inagi R, Yamauchi T, Kadowaki T, Nangaku M. Prolyl Hydroxylase Domain Inhibitor Protects against Metabolic Disorders and Associated Kidney Disease in Obese Type 2 Diabetic Mice. J Am Soc Nephrol. 2020 Mar;31(3):560-577 Sugahara M, Tanaka T, Nangaku M. Hypoxia-Inducible Factor and Oxygen Biology in the Kidney. Kidney360. 2020 Jul 22;1(9):1021-1031 Ito M, Tanaka T, Ishii T, Wakashima T, Fukui K, Nangaku M. Prolyl hydroxylase inhibition protects the kidneys from ischemia via upregulation of glycogen storage. Kidney Int. 2020 Apr;97(4):687-701 Kurata Y, Tanaka T, Nangaku M. Hypoxia-inducible factor prolyl hydroxylase inhibitor in the treatment of anemia in chronic kidney disease. Curr Opin Nephrol Hypertens. 2020 Jul;29(4):414-422 Sugahara M, Tanaka T, Nangaku M. Prolyl hydroxylase domain inhibitors as a novel therapeutic approach against anemia in chronic kidney disease. Kidney Int. 2017 Aug;92(2):306-312 Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol. 2006 Jan;17(1):17-25