Zima T, Tesar V, Crkovská J, Stejskalová A, Pláteník J, Temínová J, Nemecek K, Janebová M, Stípek S
1st Institute of Medical Chemistry and Biochemistry, First Faculty of Medicine, Charles University, Prague, Czech Republic.
Nephrol Dial Transplant. 1998 Aug;13(8):1975-9. doi: 10.1093/ndt/13.8.1975.
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 (dexrazoxan, 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.
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 ICRF-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 measure and histology of the kidney was studied after the rats were sacrificed.
Full-blown nephrotic syndrome developed after 3 weeks only in A rats. Nephrotic syndrome was completely prevented in all ICRF-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 micromol/l) and was completely normalized by ICRF-187 in CA (1.1 + 0.2 micromol/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.
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.
阿霉素代谢过程中产生的活性氧被认为在大鼠实验性阿霉素肾病的发病机制中起重要作用。ICRF - 187（右丙亚胺，Cardioxan），一种铁螯合剂，已被证明可抑制阿霉素诱导的羟自由基形成，并降低肿瘤患者的阿霉素心脏毒性。我们研究的目的是通过评估自由基在其发病机制中的可能参与情况，来评估ICRF - 187在阿霉素肾病中的假定保护作用。
我们检查了五个实验组。A组接受单次剂量的阿霉素（5mg/kg体重，静脉注射），CA组在给予阿霉素前先给予单次剂量的ICRF - 187（100mg/kg体重，静脉注射），CCA组在给予阿霉素前先给予单次剂量的ICRF - 187（同CA组），随后每周腹腔注射三次（100mg/kg体重）ICRF - 187。CC组先给予一剂ICRF - 187（100mg/kg体重，静脉注射），随后每周腹腔注射三次ICRF - 187，N组作为对照组接受生理盐水。在大鼠处死后，测量血液和肾脏匀浆中的常见生化参数、丙二醛（MDA）和抗氧化酶（谷胱甘肽过氧化物酶 - GPx和超氧化物歧化酶 - SOD），并研究肾脏组织学。
仅A组大鼠在3周后出现了典型的肾病综合征。所有接受ICRF - 187治疗的大鼠（CA组、CCA组）均完全预防了肾病综合征。与CA组（12.4 + 6.８mg/升肾小球滤液）和N组（6.1 + 3.5mg/升，P < 0.000１）相比，A组大鼠的蛋白尿显著增加（108.2 + 48.4mg/升肾小球滤液）。仅A组大鼠红细胞中的总MDA显著增加（1.7 + 0.3微摩尔/升），而ICRF - 187使CA组中的总MDA完全恢复正常（1.1 + 0.2微摩尔/升，P < 0.001）。与N组、CA组、A组相比，重复给予ICRF - 18７的组（CC组和CCA组大鼠）肾脏匀浆中的总TBARS和MDA显著升高。在阿霉素治疗的大鼠中，ICRF - 187未显著增加肾脏匀浆和红细胞中GPx和SOD的活性。A组大鼠的组织学变化类似于微小病变肾病，伴有足突融合和肾小管透明管型。在所有接受ICRF - 187治疗的大鼠组中，仅存在轻微的系膜增生和血管周围肥大细胞浸润。
我们得出结论，ICRF - 187可能通过螯合铁，完全保护大鼠免受阿霉素诱导的肾病综合征。这支持了铁介导活性氧在这种类型的肾小球损伤发展中的作用。然而，单独重复给予ICRF - 187能够增加肾脏中的氧化应激参数。
