Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-31360
Schneider, C; Krischke, G; Keller, S; Walkinshaw, G; Arend, M; Rascher, W; Gassmann, M; Trollmann, R (2009). Short-term effects of pharmacologic HIF stabilization on vasoactive and cytotrophic factors in developing mouse brain. Brain Research, 1280:43-51.
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Hypoxia-inducible transcription factors (HIFs) are crucially involved in brain development and cellular adaptation to hypoxia and ischemia. Degradation of HIF is regulated under normoxia by oxygen-dependent hydroxylation of specific prolyl residues on the labile alpha-subunit by HIF prolyl hydroxylases (PHD). Prolyl-4-hydroxylase inhibitors (PHI) have shown protective effects in vitro and in vivo in adult kidney and brain. The aim of the present study was to investigate in vivo short-term effects of a novel low molecular weight PHI, FG-4497, on HIF-regulated cytotrophic and vasoactive factors in developing mouse brain. Neonatal (P7, n=26) C57/BL6 mice were treated with PHI FG-4497 (30-100 mg/kg, i.p., duration 6 h). Gene expression was analyzed by TaqMan RT-PCR in kidney and developing brain in comparison to controls (NaCl 0.9% and non-treated animals). HIF-1alpha protein was quantified by Western blot analysis. Dose-response studies revealed prominent effects of FG-4497 at a dose of 100 mg/kg as assessed by significant up-regulation of mRNA in both kidney and brain of the following HIF-dependent genes: vascular endothelial growth factor, adrenomedullin and erythropoietin. Organ-specific transcriptional regulation was evident from analysis of hexokinase 2, inducible NO synthase and PHD3 mRNA concentrations. In the brain, HIF-1alpha and HIF-2alpha protein markedly accumulated in response to FG-4497. Besides vasoactive factors, PHI significantly increased cerebral chemokine receptor CXCR-4 mRNA levels. In conclusion, the novel PHI FG-4497 activates HIFs at an early stage of brain maturation and modulates neurotrophic processes known to be crucially involved in brain development and hypoxia-induced brain pathology.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||05 Vetsuisse Faculty > Institute of Veterinary Physiology|
04 Faculty of Medicine > Center for Integrative Human Physiology
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Deposited On:||18 Feb 2010 17:13|
|Last Modified:||23 Nov 2012 14:58|
|WoS Citation Count:||9|
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