Cisplatin-induced renal inflammation is ameliorated by cilastatin nephroprotection
Cisplatin-induced renal inflammation is ameliorated by cilastatin nephroprotection
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DOI：
10.1093/ndt/gfx005
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发表时间：
2017-10-01
影响因子：
6.1
通讯作者：
Lazaro, Alberto
中科院分区：
文献类型：
--
作者：
Humanes, Blanca;Camano, Sonia;Lazaro, Alberto
背景顺铂是一种有效的化疗药物，其肾毒性作用是抗肿瘤治疗的主要并发症和剂量限制因素。有大量证据表明，炎症有助于顺铂诱导的肾毒性的发病机制。我们发现，西司他丁，肾脱氢肽酶-I抑制剂，具有保护作用，在体外和体内对顺铂诱导的肾损伤，通过抑制细胞凋亡和氧化。在此，我们研究了西司他丁对顺铂诱导的大鼠肾损伤和炎症的潜在保护作用。雄性Wistar大鼠分为4组：对照组、西司他汀对照组、顺铂组和西司他汀-顺铂组。在顺铂给药后5天，根据血尿素氮、肌酐、肾小球滤过率（GFR）、肾损伤分子（KIM）-1和肾脏形态学评估肾毒性。采用电泳迁移率改变分析、免疫组织化学研究和炎症介质评价来测量炎症。与对照组大鼠相比，顺铂给药组大鼠受到显著的近端小管损伤、GFR降低、炎症介质产生增加以及尿素、肌酐和组织KIM-1水平升高的影响。西司他丁预防了这些肾功能的变化，并改善了顺铂给药动物的组织学损伤。西司他丁还可降低促炎细胞因子水平、核因子-κ B活化和CD 68阳性细胞浓度。西司他丁减少顺铂诱导的肾毒性，这与体内炎症减少有关。虽然减少炎症在肾保护中的确切作用尚未完全阐明，但西司他丁治疗可能是预防顺铂诱导的急性肾损伤的新策略。
Background. Cisplatin is a potent chemotherapeutic drug whose nephrotoxic effect is a major complication and a dose-limiting factor for antitumoral therapy. There is much evidence that inflammation contributes to the pathogenesis of cisplatin-induced nephrotoxicity. We found that cilastatin, a renal dehydropeptidase-I inhibitor, has protective effects in vitro and in vivo against cisplatin-induced renal damage by inhibiting apoptosis and oxidation. Here, we investigated the potential use of cilastatin to protect against cisplatin-induced kidney injury and inflammation in rats.Methods. Male Wistar rats were divided into four groups: control, cilastatin-control, cisplatin and cilastatin-cisplatin. Nephrotoxicity was assessed 5 days after administration of cisplatin based on blood urea nitrogen, creatinine, glomerular filtration rate (GFR), kidney injury molecule (KIM)-1 and renal morphology. Inflammation was measured using the electrophoretic mobility shift assay, immunohistochemical studies and evaluation of inflammatory mediators.Results. Compared with the control rats, cisplatin-administered rats were affected by significant proximal tubule damage, decreased GFR, increased production of inflammatory mediators and elevations in urea, creatinine and tissue KIM-1 levels. Cilastatin prevented these changes in renal function and ameliorated histological damage in cisplatin-administered animals. Cilastatin also reduced pro-inflammatory cytokine levels, activation of nuclear factor-kappa B and CD68-positive cell concentrations.Conclusions. Cilastatin reduces cisplatin-induced nephrotoxicity, which is associated with decreased inflammation in vivo. Although the exact role of decreased inflammation in nephroprotection has not been fully elucidated, treatment with cilastatin could be a novel strategy for the prevention of cisplatin-induced acute kidney injury.