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

Abstract

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

The von Hippel–Lindau tumor suppressor gene product represses oncogenic β-catenin signaling in renal carcinoma cells

“…VHL is then re-expressed upon completion of renal tubulogenesis throughout the tubular epithelium (34). In contrast, the expression patterns of HIF-1␣ and HIF-2␣ are consistent with roles in promoting tubulogenesis and vasculogenesis, but upon completion of nephrogenesis HIF-1␣ and HIF-2␣ become undetectable, consistent with proteosomal targeting by upregulated pVHL expression (36). Under normoxic conditions, tight control of HIF levels by pVHL persists in adulthood; when VHL function is lost, aberrant HIF target gene expression and other molecular changes contribute to oncogenesis (2,5).…”

Kidney development and gene expression in the HIF2α knockout mouse

“…In developing kidney, where VEGF signaling is critical for normal glomerular differentiation, we observed HIF1␣ and -2␣ mRNA expression in the nephrogenic zone of the outer cortex (Freeburg et al, 2003). Although originally thought to be confined to endothelial cells (Tian et al, 1997), HIF2␣ expression has also been localized to immature podocytes, suggesting that it may play a role in glomerular capillary development (Freeburg et al, 2003;Bernhardt et al, 2006). In addition, HIF2␣ protein is stably expressed in avascular embryonic kidney explants, and is up-regulated by hypoxia, which also causes an increase in VEGF mRNA (Freeburg et al, 2003).…”

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

“…In the fully developed normal kidney, HIF-1α expression is maintained, while HIF-2α expression has disappeared. The role of HIF-signaling during development is largely unclear, but the cell type-and stage-specific expression distribution of HIF-α subunits correlates with the expression of critical angiogenic factors such as VEGF and endoglin (Freeburg and Abrahamson 2003;Bernhardt et al 2006). Conditional knockouts in renal proximal tubule cells of either HIF-1α or HIF-β alone do not generate an abnormal phenotype, whereas conditional knockout of pVHL results in HIF-dependent development of tubular and glomerular cysts (Rankin et al 2006).…”