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Early kidney development is associated with the coordinated branching of the renal tubular and vascular system and hypoxia has been proposed to be a major regulatory factor in this process. Under low oxygen levels, the hypoxia-inducible transcription factor (HIF) regulates the expression of genes involved in angiogenesis, erythropoiesis and glycolysis. To investigate the role of HIF in kidney development, we analyzed the temporal and spatial expression of the oxygen regulated HIF-1α and -2α subunits at different stages of rat and human kidney development. Using double-staining procedures, localization of the HIF target geneproducts vascular endothelial growth factor (VEGF) and endoglin was studied in relation to HIFα. In both species, we found marked nuclear expression of HIF-1α in medullary and cortical collecting ducts and in glomerular cells. In contrast, HIF-2α was expressed in interstitial and peritubular cells podocytes of the more mature glomeruli. After completion of glomerulogenesis and nephrogenesis, HIF-1α and -2α were no longer detectable. The HIF-target gene VEGF colocalized with HIF-1α protein in glomeruli and medullary collecting ducts. HIF-2α colocalized with the endothelium-associated angiogenic factor, endoglin. Both HIFα isoforms are activated in the developing kidney in a cell-specific and temporally controlled manner, indicating a regulatory role of oxygen tension in nephrogenesis. HIF-1α seems to be primarily involved in tubulogenesis and HIF-2α in renal vasculogenesis. Both isoforms are found in glomerulogenesis, potentially having synergistic effects.Kidney International (2006) 69, 114–122. doi:10.1038/sj.ki.5000062 [ABSTRACT FROM AUTHOR]