Francescato Heloísa D C, Costa Roberto S, Júnior Fernando Barbosa, Coimbra Terezila M
Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Nephrol Dial Transplant. 2007 Aug;22(8):2138-48. doi: 10.1093/ndt/gfm144. Epub 2007 Apr 16.
Cisplatin therapy is effective against many tumours, however, the nephrotoxicity of this drug is a dose-limiting factor. Apoptosis and necrosis of tubular cells and inflammatory events contribute to the cisplatin-induced nephrotoxicity. Cisplatin promotes increased production of reactive oxygen species, which can activate c-jun N-terminal kinase (JNK) that is a mediator of apoptosis and can lead to increased expression of proinflammatory mediators that could intensify the cytotoxic effects of cisplatin. In this study, we evaluated the effect that SP600125, a selective inhibitor of phosphorylated JNK (p-JNK), has on the renal damage caused by cisplatin use.
A total of 33 male Wistar rats received SP600125 (15 mg/kg/day, s.c., diluted in polyethylene glycol) for 4 days. At 24 h after the first dose, those 33 rats, plus an additional 30, were injected with cisplatin (5 mg/kg, i.p.). In addition, 18 control rats were injected with saline, and 12 rats with polyethylene glycol. At 2 and 5 days after saline or cisplatin injection, blood and urine samples were collected for measurement of creatinine, sodium and potassium, and the kidneys removed for histological, immunohistochemical and Western blot studies.
Cisplatin-treated rats presented higher plasma creatinine, as well as greater immunostaining for ED1 (macrophages/monocytes), p-JNK, apoptotic cells, and tubular cell necrosis in the renal cortices and outer medullae. The increase of p-JNK expression was also confirmed by Western blot analysis. All of these alterations were attenuated by treatment with SP600125.
The protective effect of SP600125 on cisplatin-induced renal damage seems to be related to the reduction in the apoptotic cell death and to the restriction of renal inflammation.
顺铂疗法对许多肿瘤有效，然而，该药物的肾毒性是一个剂量限制因素。肾小管细胞的凋亡和坏死以及炎症反应导致了顺铂诱导的肾毒性。顺铂促进活性氧的产生增加，活性氧可激活c-jun氨基末端激酶（JNK），JNK是细胞凋亡的介质，可导致促炎介质表达增加，从而增强顺铂的细胞毒性作用。在本研究中，我们评估了磷酸化JNK（p-JNK）的选择性抑制剂SP600125对顺铂使用所致肾损伤的影响。
总共33只雄性Wistar大鼠接受SP600125（15mg/kg/天，皮下注射，用聚乙二醇稀释），持续4天。在首次给药后24小时，这33只大鼠以及另外30只大鼠腹腔注射顺铂（5mg/kg）。此外，18只对照大鼠注射生理盐水，12只大鼠注射聚乙二醇。在注射生理盐水或顺铂后第2天和第5天，采集血液和尿液样本以测定肌酐、钠和钾，并取出肾脏进行组织学、免疫组织化学和蛋白质印迹研究。
顺铂处理的大鼠血浆肌酐水平更高，肾皮质和外髓中ED1（巨噬细胞/单核细胞）、p-JNK、凋亡细胞和肾小管细胞坏死的免疫染色更强。蛋白质印迹分析也证实了p-JNK表达的增加。所有这些改变都通过SP600125治疗得到了减轻。
SP600125对顺铂诱导的肾损伤的保护作用似乎与凋亡细胞死亡的减少和肾炎症的限制有关。
