Document Detail


Comparing the potential renal protective activity of desferrioxamine B and the novel chelator desferrioxamine B-N-(3-hydroxy-adamant-1-yl)carboxamide in a cell model of myoglobinuria.
MedLine Citation:
PMID:  21320071     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Accumulating myoglobin (Mb) in the kidney following severe burns promotes oxidative damage and inflammation leading to acute renal failure. The potential for haem-iron to induce oxidative damage has prompted testing of iron chelators (e.g. desferrioxamine B (DFOB)) as renal protective agents. We compared the ability of DFOB and a DFOB-derivative (DFOB-AdAOH) to protect renal epithelial cells from Mb insult. Loading kidney-tubule epithelial cells with dihydrorhodamine-123 before exposure to 100microM Mb increased rhodamine-123 fluorescence relative to controls (minus Mb) indicating increased oxidative stress. Extracellular Mb elicited a reorganisation of transferrin receptor as assessed by monitoring labelled transferrin uptake with flow cytometry and inverted-fluorescence microscopy. Myoglobin stimulated haemoxygenase-1 (HO-1), tumor necrosis factor-a (TNF-a), and both intracellular (ICAM) and vascular (VCAM) adhesion molecule-1 gene expression and inhibited epithelial monolayer permeability. Pre-treatment with DFOB or DFOB-AdAOH decreased Mb-mediated rhodamine-123 fluorescence, HO-1, ICAM and TNF-a gene expression and restored monolayer permeability. Monocyte chemotactic protein-1 secretion increased in cells exposed to Mb-insult and this was abrogated by DFOB or DFOB-AdAOH. Cells treated with DFOB or DFOB-AdAOH alone showed no change in permeability, MCP-1 secretion or HO-1, TNF-a, ICAM or VCAM gene expression. Similar to DFOB, incubation of DFOB-AdAOH with Mb plus H2O2 yielded nitroxide radicals as detected by electron paramagnetic resonance spectroscopy indicating a potential antioxidant activity in addition to metal chelation: Fe(III) loaded DFOB-AdAOH showed no nitroxide radical formation. Overall, the chelators inhibited Mb-induced oxidative stress and inflammation and improved epithelial cell function. DFOB-AdAOH showed similar activity to DFOB indicating that this novel, low-toxicity chelator may protect the kidney after severe burns.
Authors:
Ludwig K Groebler; Joe Liu; Anu Shanu; Rachel Codd; Paul Kenneth Witting
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-2-14
Journal Detail:
Title:  The Biochemical journal     Volume:  -     ISSN:  1470-8728     ISO Abbreviation:  -     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-2-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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