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Action of hypoxia-inducible factor in liver and kidney from mice with Pax8-rtTA-based deletion of von Hippel-Lindau protein.
MedLine Citation:
PMID:  23384425     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
AIM: 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:
S Mathia; A Paliege; R Koesters; H Peters; H-H Neumayer; S Bachmann; C Rosenberger
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Acta physiologica (Oxford, England)     Volume:  207     ISSN:  1748-1716     ISO Abbreviation:  Acta Physiol (Oxf)     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-06     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101262545     Medline TA:  Acta Physiol (Oxf)     Country:  England    
Other Details:
Languages:  eng     Pagination:  565-76     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors Acta Physiologica © 2012 Scandinavian Physiological Society.
Affiliation:
Department of Nephrology and Renal Transplantation, Charité-Universitaetsmedizin Berlin, Berlin, Germany.
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