Nephrology Dialysis Transplantation, Vol 13, Issue 8 1975-1979, Copyright © 1998 by Oxford University Press
T Zima, V Tesar, J Crkovska, A Stejskalova, J Platenik, J Teminova, K Nemecek, M Janebova and S Stipek
Background. Reactive oxygen species produced during
metabolism of adriamycin are purported to play an important role in the
pathogenesis of experimental adriamycin nephropathy in rats. ICRF-187
(dextrazoxan, Cardioxan), an iron chelator, has been shown to inhibit
adriamycin-induced formation of hydroxyl radical and to decrease adriamycin
cardiotoxicity in oncological patients. The aim of our study was to assess
the putative protective role of ICRF-187 in adriamycin nephropathy by
evaluating the possible participation of free radicals in its pathogenesis.
Methods. We examined five experimental groups. Group
A, received a single dose of adriamycin (5 mg/kg bw i.v.), group CA was
given a single dose of ICRF-187 (100 mg/kg bw i.v.) before adriamycin
administration, group CCA received a single dose of ICR-187 (100 mg/kg bw
i.v.) before adriamycin administration followed by three weekly
intraperitoneal injections (100 mg/kg bw) ICRF-187. Group CC received one
dose of ICRF-187 (100 mg/kg bw i.v.) followed by three weekly
intraperitoneal injections of ICRF-187, and group N served as control
receiving saline. Common biochemical parameters, malondialdehyde (MDA) and
antioxidant enzymes (glutathione peroxidase-GPx and superoxide
dismutase-SOD) in blood and kidney homogenates were measured and histology
of the kidney was studied after the rats were sacrificed.
Results. Full-blown nephrotic syndrome developed after
3 weeks only in A rats. Nephrotic syndrome was completely prevented in all
ICR-187 treated rats (CA, CCA). Proteinuria was significantly increased in
A rats (108.2 + 48.4 mg/l of glomerular filtrate) compared with CA (12.4 +
6.8 mg/l, P <0.0001) and with N (6.1 + 3.5
mg/l, P < 0.0001). Total MDA in erythrocytes
was significantly increased only in A rats (1.7 + 0.3 &mgr;mol/l) and
was completely normalized by ICRF-187 in CA (1.1 + 0.2 &mgr;mol/l,
P <0.001). Total TBARS and MDA in kidney
homogenates were significantly elevated in groups with repeated
administration of ICRF-187 (CC and CCA rats) compared to N, CA, A groups.
Activity of GPx and SOD in kidney homogenate and in erythrocytes was not
significantly increased by ICRF-187 in adriamycin treated rats. Histologic
changes in A rats resembled minimal change nephropathy with fusion of foot
processes and hyaline casts in tubules. There was only minimal mesangial
proliferation and perivascular mast cell infiltrates in all groups of
ICRF-187-treated rats. Conclusions. We conclude that
ICRF-187, probably by chelation iron, completely protected rats from
adriamycin-induced nephrotic syndrome. It supports the role of
iron-mediated reactive oxygen species in the development of this type of
glomerular injury. However, repeated administration of ICRF-187 alone is
able to increase parameters of oxidative stress in the kidney.
Keywords: adriamycin nephropathy; Cardioxan;
glutathione peroxidase; ICRF-187; lipid peroxidation; superoxide dismutase
ORIGINAL ARTICLES
ICRF-187 (dextrazoxan) protects from adriamycin-induced nephrotic syndrome in rats
1st Institute of Medical Chemistry and Biochemistry, 1st Department of Medicine, 1st Institute of Pathology, 2nd Department of Medicine, First Faculty of Medicine, Charles University, and Institute of Clinical and Experimental Medicine, Prague, Czech Republic; Correspondence to: T Zima, 1st Institute of Medical Chemistry and Biochemistry, First Faculty of Medicine, Charles University, Katerinska 32, CZ-120 00 Prague, Czech Republic
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