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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]

Aim Cyclosporin A (CsA) causes renal toxicity. The underlying mechanisms are incompletely understood, but may involve renal hypoxia and hypoxia-inducible factors (Hifs). We sought for hypoxia and Hif in mouse kidneys with CsA-induced toxicity, assessed their time course, Hif-mediated responses and the impact of interventional Hif upregulation. Methods Mice received CsA or its solvent cremophore for up to 6 weeks. Low salt diet (Na+↓) was given in combination with CsA to enhance toxicity. We assessed fine morphology, renal function, blood oxygen level-dependent magnetic resonance imaging under room air and following changes in breathing gas composition which correlate with vascular reactivity, pimonidazole adducts (which indicate O2 tensions below 10 mmHg), Hif- α proteins, as well as expression of Hif target genes. Stable Hif upregulation was achieved by inducible, Pax8-rt TA-based knockout of von Hippel-Lindau protein (Vhl- KO), which is crucial for Hif- α degradation. Results Cyclosporin A transiently increased renal deoxyhaemoglobin (R2*). Augmented vascular reactivity was observed at 2 h, but decreased at 24 h after CsA treatment. Na+↓/CsA provoked chronic renal failure with tubular degeneration and interstitial fibrosis. Nephron segments at risk for injury accumulated pimonidazole adducts, as well as Hif- α proteins. Remarkably, Hif target gene expression remained unchanged, while factor-inhibiting Hif (Fih) was enhanced. Na+↓/CsA/Vhl- KO aggravated morpho-functional outcome of chronic renal CsA toxicity. Conclusions Cyclosporin A provokes episodic hypoxia in nephron segments most susceptible to chronic CsA toxicity. Fih is upregulated and likely blocks further Hif activity. Continuous tubular Hif upregulation via Vhl- KO worsens the outcome of chronic CsA-induced renal toxicity. [ABSTRACT FROM AUTHOR]

Aim: In acute kidney injury (AKI), regions of the kidney are hypoxic. However, for reasons yet unknown, adaptation to hypoxia through hypoxia‐inducible factor (HIF) is limited. Here, we studied miR‐22, a potential HIF repressor, in normal kidneys, as well as in rhabdomyolysis‐induced AKI, a condition where miR‐22 is up‐regulated. Methods: AKI in mice was provoked by IM injection of glycerol. Tissue homogenates were processed to determine the levels of candidate RNAs and proteins, as well as global gene expression profiles. Reporter assays quantified in vitro miR‐22 activity and its modulation by mimic or inhibitor molecules, under normoxia or hypoxia (1% O2) respectively. In vivo, anti–miR‐22 molecules were applied to normal mice or prior to induction of AKI. Renal outcome was assessed by measuring plasma creatinine, plasma urea and the levels of the injury markers Kim‐1 and Ngal. Results: Renal miR‐22 is inducible by hypoxia and represses hypoxia‐inducible factor (HIF). Specific inhibition of miR‐22 regulates 1913 gene transcripts in kidneys controls and 3386 in AKI, many of which are involved in development or carcinogenesis. Specific inhibition of miR‐22 up‐regulates tissue protective HIF target genes, yet renal function and injury markers are unchanged or worsened. Conclusions: miR‐22 is a HIF repressor constitutively expressed in the adult kidney and up‐regulated in AKI. Specific inhibition of miR‐22 is efficient in vivo and profoundly affects renal gene expression in health and disease, including up‐regulation of HIF. However, the net effect on rhabdomyolysis‐induced AKI outcome is neutral or even negative. [ABSTRACT FROM AUTHOR]