Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transgenic overexpression of Tcfap2c/AP-2gamma results in liver steatosis

ABSTRACT: We established a mouse model, in which transcription factor Tcfap2c can be activated in an inducible and reversible manner in somatic tissues, taking advantage of the tetracycline-dependent regulatory system. Induction of the transgene led to robust expression in all tissues (except brain and testis) and lead to rapid mortality within 3-7 days. In the liver, accumulation of microvesicular lipid droplets and breakdown of major hepatic metabolism pathways resulted in steatosis. Transgenic and control mice were treated with doxycycline (1mg/d i.p.) three times (0, 24 and 48h) and liver samples were collected after 52h. In addition, primary hepatocytes isolated from transgenic and control animals were cultured with doxycycline for 3 days (1µg/ml).

ORGANISM(S): Mus musculus

SUBMITTER: Peter Kuckenberg

PROVIDER: E-GEOD-28692 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Transgenic overexpression of Tcfap2c/AP-2gamma results in liver failure and intestinal dysplasia.

Holl Daniel D Kuckenberg Peter P Woynecki Tatiana T Egert Angela A Becker Astrid A Huss Sebastian S Stabenow Dirk D Zimmer Andreas A Knolle Percy P Tolba René R Fischer Hans-Peter HP Schorle Hubert H

PloS one 20110713 7

<h4>Background</h4>The transcription factor Tcfap2c has been demonstrated to be essential for various processes during mammalian development. It has been found to be upregulated in various undifferentiated tumors and is implicated with poor prognosis. Tcfap2c is reported to impinge on cellular proliferation, differentiation and apoptosis. However, the physiological consequences of Tcfap2c-expression remain largely unknown.<h4>Methodology/principal findings</h4>Therefore we established a gain of ...[more]

PMID: 21779369

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Project 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.

Dataset Information

Transgenic overexpression of Tcfap2c/AP-2gamma results in liver steatosis

Publications

Transgenic overexpression of Tcfap2c/AP-2gamma results in liver failure and intestinal dysplasia.

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