title: Action of hypoxia-inducible factor in liver and kidney from mice with Pax8-rtTA-based deletion of von Hippel-Lindau protein.
abstract: OBJECTIVE
  Von Hippel-Lindau protein (VHL) provides the degradation of hypoxia-inducible factor (HIF). Tetracycline-induced, Pax8-rtTA-based knockout of VHL (VHL-KO) affects all renal tubules and periportal hepatocytes and leads to sustained upregulation of HIF. Here, we study the phenotype of VHL-KO in both organs, the time course of changes, and long-term morpho-functional outcome.
  
  
  METHODS
  Mice with doxycycline-induced VHL-KO and controls (CON) were followed for up to 9 months. Systemic and tissue parameters were evaluated using clinical chemistry, histology, immunohistochemistry, RT-PCR and in situ hybridisation.
  
  
  RESULTS
  At day 3 following VHL-KO, substantial abundance of HIF-1α and -2α was detected in the nuclei of hepatocytes and renal tubular epithelia. Hypoxia, induced by bleeding anaemia, did not further augment HIF signal. Erythropoietin mRNA was detectable in hepatocytes but not in the kidney. Vascular endothelial growth factor mRNA was upregulated in kidney but not in liver. At day 7 following VHL-KO, the renal capillary density was enhanced, reaching its maximum at day 14. Blood haemoglobin increased constantly up to day 28 (23.3 vs. 15.8 g dL(-1) , VHL-KO vs. CON). Thereafter, it was kept within the normal range by weekly blood collections. Pathological changes were absent from kidney and liver 9 months after VHL-KO.
  
  
  CONCLUSIONS
  Inducible, Pax8-rtTA-based deletion of VHL leads to organ-specific expression of epithelial HIF and erythropoietin in liver and kidney without causing pathological changes. Uniform, maximal and sustained HIF activation along the renal tubule may serve to study the potential benefits of hypoxia adaptation in experimental renal injury.
authors: Department of Nephrology and Renal Transplantation, Charité-Universitaetsmedizin Berlin, Berlin, Germany.
authors: S
authors: S
authors: Mathia
authors: A
authors: A
authors: Paliege
authors: R
authors: R
authors: Koesters
authors: H
authors: H
authors: Peters
authors: H-H
authors: HH
authors: Neumayer
authors: S
authors: S
authors: Bachmann
authors: C
authors: C
authors: Rosenberger
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism; D004920:Erythropoiesis; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D006454:Hemoglobins / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007668:Kidney / Q000098:blood supply / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D006454:Hemoglobins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D012333:RNA, Messenger; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C499496:Pax8 protein, mouse; C467480:vascular endothelial growth factor A, mouse; C494469:VHL protein, mouse