Expression of hypoxia-inducible transcription factors in developing human and rat kidneys

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-1 alpha and -2 alpha 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 HIF alpha. In both species, we found marked nuclear expression of HIF-1 alpha in medullary and cortical collecting ducts and in glomerular cells. In contrast, HIF-2 alpha was expressed in interstitial and peritubular cells podocytes of the more mature glomeruli. After completion of glomerulogenesis and nephrogenesis, HIF-1 alpha and -2 alpha were no longer detectable. The HIF-target gene VEGF colocalized with HIF-1 alpha protein in glomeruli and medullary collecting ducts. HIF-2 alpha colocalized with the endothelium-associated angiogenic factor, endoglin. Both HIF alpha 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-1 alpha seems to be primarily involved in tubulogenesis and HIF-2 alpha in renal vasculogenesis. Both isoforms are found in glomerulogenesis, potentially having synergistic effects.