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Effects of deferasirox on renal function and renal epithelial cell death.

Abstract
Iron-chelating therapy results in a significant improvement in the life expectancy of patients with transfusional iron overload. However, alterations of renal function have been observed in some patients undergoing chelation therapy. In the present study we evaluated the effect of treatment with deferasirox iron chelator on the renal function in normal Wistar rats and in mouse and human cultured tubular cell lines. Results indicate that deferasirox given daily via intraperitoneal route for 7 days induced: (1) an increased urinary protein, albumin and glucose excretion, (2) tubular necrosis/apoptosis, (3) and increased tubular damage markers, in spite of normal glomerular function. Moreover, in vitro studies revealed that: (1) mouse MCT cultures resulted more susceptible to the antiproliferative/cytotoxic effect of deferasirox, mainly at 24h after treatment, than human HK-2 cultures, (2) MCT cell content of damage molecules increased after 24h of iron chelator treatment with slight changes in their excretion into the culture medium and (3) MCT cultures showed a significant evidence of apoptotic cell death through an increased expression and activation of caspase-3 and marked DNA fragmentation. In conclusion, this renal side effect of deferasirox-chelating therapy seems to be based on direct toxic effects of deferasirox on renal tubular cells.
AuthorsPenélope D Sánchez-González, Francisco J López-Hernandez, Ana I Morales, Juan F Macías-Nuñez, Jose M López-Novoa
JournalToxicology letters (Toxicol Lett) Vol. 203 Issue 2 Pg. 154-61 (Jun 10 2011) ISSN: 1879-3169 [Electronic] Netherlands
PMID21439361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • Benzoates
  • Cell Adhesion Molecules
  • Clu protein, rat
  • Clusterin
  • Cystatin C
  • Havcr1protein, rat
  • Iron Chelating Agents
  • Lipocalins
  • Triazoles
  • Acetylglucosaminidase
  • Deferasirox
Topics
  • Acetylglucosaminidase (urine)
  • Animals
  • Apoptosis (drug effects)
  • Benzoates (toxicity)
  • Cell Adhesion Molecules (urine)
  • Cell Line
  • Chick Embryo
  • Clusterin (urine)
  • Cystatin C (urine)
  • Deferasirox
  • Epithelial Cells (drug effects, pathology)
  • Glomerular Filtration Rate (drug effects)
  • Histocytochemistry
  • Iron Chelating Agents (toxicity)
  • Kidney (drug effects, pathology)
  • Kidney Diseases (chemically induced, pathology, urine)
  • Lipocalins (urine)
  • Male
  • Rats
  • Rats, Wistar
  • Triazoles (toxicity)

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