PMID- 21320071
OWN - NLM
STAT- MEDLINE
DCOM- 20110707
LR  - 20131121
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 435
IP  - 3
DP  - 2011 May 1
TI  - Comparing the potential renal protective activity of desferrioxamine B and the 
      novel chelator desferrioxamine B-N-(3-hydroxyadamant-1-yl)carboxamide in a cell 
      model of myoglobinuria.
PG  - 669-77
LID - 10.1042/BJ20101728 [doi]
AB  - Accumulating Mb (myoglobin) in the kidney following severe burns promotes 
      oxidative damage and inflammation, which leads to acute renal failure. The 
      potential for haem-iron to induce oxidative damage has prompted testing of iron 
      chelators [e.g. DFOB (desferrioxamine B)] as renal protective agents. We compared 
      the ability of DFOB and a DFOB-derivative DFOB-AdAOH 
      [DFOB-N-(3-hydroxyadamant-1-yl)carboxamide] to protect renal epithelial cells 
      from Mb insult. Loading kidney-tubule epithelial cells with dihydrorhodamine-123 
      before exposure to 100 muM Mb increased rhodamine-123 fluorescence relative to 
      controls (absence of Mb), indicating increased oxidative stress. Extracellular Mb 
      elicited a reorganization of the transferrin receptor as assessed by monitoring 
      labelled transferrin uptake with flow cytometry and inverted fluorescence 
      microscopy. Mb stimulated HO-1 (haem oxygenase-1), TNFalpha (tumour necrosis factor 
      alpha), and both ICAM (intercellular adhesion molecule) and VCAM (vascular cell 
      adhesion molecule) gene expression and inhibited epithelial monolayer 
      permeability. Pre-treatment with DFOB or DFOB-AdAOH decreased Mb-mediated 
      rhodamine-123 fluorescence, HO-1, ICAM and TNFalpha gene expression and restored 
      monolayer permeability. MCP-1 (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, TNFalpha, ICAM or VCAM gene expression. 
      Similarly to DFOB, incubation of DFOB-AdAOH with Mb plus H2O2 yielded nitroxide 
      radicals as detected by EPR 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.
FAU - Groebler, Ludwig K
AU  - Groebler LK
AD  - Discipline of Pathology, Redox Biology Group and Bosch Institute, The University 
      of Sydney, Sydney, NSW 2006, Australia.
FAU - Liu, Joe
AU  - Liu J
FAU - Shanu, Anu
AU  - Shanu A
FAU - Codd, Rachel
AU  - Codd R
FAU - Witting, Paul K
AU  - Witting PK
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Chelating Agents)
RN  - 0 (Myoglobin)
RN  - J06Y7MXW4D (Deferoxamine)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Chelating Agents/*pharmacology
MH  - Deferoxamine/*analogs & derivatives/*pharmacology
MH  - Dogs
MH  - Endocytosis
MH  - Epithelial Cells/*drug effects
MH  - Gene Expression Regulation/drug effects/physiology
MH  - Kidney Tubules/*cytology
MH  - Molecular Structure
MH  - Myoglobin/toxicity
MH  - Myoglobinuria/*drug therapy
EDAT- 2011/02/16 06:00
MHDA- 2011/07/08 06:00
CRDT- 2011/02/16 06:00
PHST- 2011/02/16 06:00 [entrez]
PHST- 2011/02/16 06:00 [pubmed]
PHST- 2011/07/08 06:00 [medline]
AID - BJ20101728 [pii]
AID - 10.1042/BJ20101728 [doi]
PST - ppublish
SO  - Biochem J. 2011 May 1;435(3):669-77. doi: 10.1042/BJ20101728.