title: Iron distribution and histopathological study of the effects of deferoxamine and deferiprone in the kidneys of iron overloaded β-thalassemic mice.
abstract: Renal glomerular and tubular dysfunctions have been reported with high prevalence in β-thalassemia. Iron toxicity is implicated in the kidney damage, which may be reversed by iron chelation therapy. To mimic heavy iron overload and evaluate the efficacy of iron chelators in the patients, iron dextran (180mg iron/mouse) was intraperitoneally (i.p.) injected in heterozygous β-globin knockout mice ((muβth-3/+), BKO) and wild type mice (C57BL/6J, WT) over a period of 2 weeks, followed by daily i.p. injection of deferoxamine (DFO) or deferiprone (L1) for 1 week. In BKO mice, iron preferentially accumulated in the proximal tubule with a grading score of 0-1 and increased to grade 3 after iron loading. In contrast, iron mainly deposited in the glomerulus and interstitial space in iron overloaded WT mice. Increased levels of kidney lipid peroxidation, glomerular and medullar damage and fibrosis in iron overloaded mice were reversed by treatment with iron chelators. L1 showed higher efficacy than DFO in reduction of glomerular iron, which was supported by a significantly decreased the amount of glomerular damage. Notably, DFO and L1 demonstrated a distinct pattern of iron distribution in the proximal tubule of BKO mice. In conclusion, chelation therapy has beneficial effects in iron-overloaded kidneys. However, the defect of kidney iron metabolism in thalassemia may be a determining factor of the treatment outcome in individual patients.
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; Department of Pre-clinic and Applied Animal Science, Faculty of Veterinary Science, Mahidol University, Nakhon Pathom 73170, Thailand.
authors.forename: Paranee
authors.initials: P
authors.lastname: Yatmark
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand. Electronic address: noppawan.phu@mahidol.ac.th.
authors.forename: Noppawan Phumala
authors.initials: NP
authors.lastname: Morales
authors.affiliation: Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Urai
authors.initials: U
authors.lastname: Chaisri
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Surasak
authors.initials: S
authors.lastname: Wichaiyo
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Warinkarn
authors.initials: W
authors.lastname: Hemstapat
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Somdet
authors.initials: S
authors.lastname: Srichairatanakool
authors.affiliation: Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Salaya Campus, Nakhon Pathom 73170, Thailand.
authors.forename: Saovaros
authors.initials: S
authors.lastname: Svasti
authors.affiliation: Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Salaya Campus, Nakhon Pathom 73170, Thailand.
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
mesh_terms: D000818:Animals; D000077543:Deferiprone; D003676:Deferoxamine / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D007501:Iron / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D011728:Pyridones / Q000008:administration & dosage / Q000627:therapeutic use*; D014018:Tissue Distribution; D055544:beta-Globins / Q000235:genetics; D017086:beta-Thalassemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D007502:Iron Chelating Agents; D011728:Pyridones; D055544:beta-Globins; D000077543:Deferiprone; D007501:Iron; D003676:Deferoxamine
keywords: Beta-knockout mice; Deferiprone; Deferoxamine; Iron overload; Kidney pathology