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E-GEOD-44925 - HIF orchestrated metabolic shift confers protection against Acute Kidney Injury (AKI)

Status
Released on 5 September 2013, last updated on 26 September 2013
Organism
Mus musculus
Samples (16)
Array (1)
Protocols (7)
Description
Renal hypoxia is widespread in acute kidney injury (AKI) of various aetiologies. Hypoxia adaptation, conferred through the hypoxia-inducible factor (HIF), appears to be insufficient. Here we show that HIF activation in renal tubules through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO) protects from rhabdomyolysis-induced AKI. In this model, histological observations indicate that injury mainly affects proximal convoluted tubules, with 5% necrosis at d1 and 40% necrosis at d2. HIF-1alpha up-regulation in distal tubules reflects renal hypoxia. However, lack of HIF in proximal tubules suggests insufficient adaptation by HIF. AKI in VHL-KO mice leads to prominent HIF activation in all nephron segments, as well as to reduced serum creatinine, serum urea, tubular necrosis, and apoptosis marker caspase-3 protein. At d1 after rhabdomyolysis, when tubular injury is potentially reversible, HIF mediated protection in AKI is associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal as demonstrated by qPCR, pathway enrichment analysis and immunohistochemistry. Together, our data provide evidence for a HIF-orchestrated multi-level shift towards glycolysis as a major mechanism for protection against acute tubular injury. All experiments were carried out in transgenic mice in which selective renal tubular VHL knockout (VHL-KO) was inducible by doxycycline (Reference: Mathia S, Paliege A, Koesters R, Peters H, Neumayer HH, Bachmann S, Rosenberger C. Action of hypoxia-inducible factor in liver and kidney from mice with Pax8-rtTA-based deletion of von Hippel-Lindau protein. Acta Physiol (Oxf). 2013; 207(3):565-76.). Four groups of animals were used: 1) controls: untreated mice; 2) VHL-KO: injected with doxycycline (0.1 mg per 10 g body weight SC), 4 days prior to sacrifice; 3) AKI: rhabdomyolysis; 4) VHL-KO/AKI: doxycycline plus rhabdomyolysis. To induce AKI, 50% glycerol (0.05 ml per 10 g body weight) was injected IM into the left hind limb under isoflurane narcosis. Drinking water was withdrawn between 20 h prior and 24 h after glycerol injection.
Experiment type
transcription profiling by array 
Contacts
Alexander Paliege, Christian Rosenberger, Hans H Neumayer, Harm Peters, Michael Fähling, Pontus B Persson, Ralf Mrowka, Robert Koesters, Sebastian Bachmann, Susanne Mathia
Citation
Tubular von Hippel-Lindau Knockout Protects against Rhabdomyolysis-Induced AKI. F�hling M, Mathia S, Paliege A, Koesters R, Mrowka R, Peters H, Persson PB, Neumayer HH, Bachmann S, Rosenberger C. , PMID:23970125
MIAME
PlatformsProtocolsVariablesProcessedRaw
Files
Investigation descriptionE-GEOD-44925.idf.txt
Sample and data relationshipE-GEOD-44925.sdrf.txt
Raw data (1)E-GEOD-44925.raw.1.zip
Processed data (1)E-GEOD-44925.processed.1.zip
Array designA-AFFY-130.adf.txt
Links