Megalin Blockade with Cilastatin Suppresses Drug-Induced Nephrotoxicity
Megalin Blockade with Cilastatin Suppresses Drug-Induced Nephrotoxicity
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DOI：
10.1681/asn.2016060606
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发表时间：
2017-06-01
影响因子：
13.6
通讯作者：
Saito, Akihiko
中科院分区：
文献类型：
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作者：
Hori, Yoshihisa;Aoki, Nobumasa;Saito, Akihiko
抗微生物或抗癌药物引起的肾毒性是一个严重的临床问题。Megalin是一种在近端小管顶端膜表达的内吞受体，介导氨基糖苷类和粘菌素（多重耐药微生物的关键抗菌剂）的肾毒性。万古霉素（耐甲氧西林金黄色葡萄球菌的抗菌剂）和顺铂（一种重要的抗癌药物）诱导肾毒性的机制尚不清楚，尽管这些药物和庆大霉素（一种氨基糖苷类）的肾毒性在实验中被西司他丁抑制。在临床环境中，西司他丁已被安全地用于抑制脱氢肽酶-I介导的亚胺培南（一种碳青霉烯类抗菌剂）的肾代谢，从而限制肾小管损伤。在这里，我们测试了西司他丁也阻断巨蛋白介导的万古霉素、顺铂、粘菌素和氨基糖苷类药物的摄取，从而限制这些药物的肾毒性的假设。石英晶体微量天平分析表明，巨蛋白也结合万古霉素和顺铂，西司他丁与巨蛋白竞争结合庆大霉素，粘菌素，万古霉素和顺铂。在用粘菌素、万古霉素或顺铂处理的肾特异性镶嵌性巨蛋白基因敲除小鼠中，充满巨蛋白的近端小管上皮细胞表现出损伤迹象，而巨蛋白缺陷细胞则没有。此外，同时给予西司他丁抑制了C57 BL/6 J小鼠中粘菌素诱导的肾毒性。值得注意的是，西司他丁在体外不抑制庆大霉素、粘菌素或万古霉素的抗菌活性，就像在先前的研究中西司他丁不影响顺铂的抗癌活性一样。总之，用西司他丁阻断巨蛋白可有效抑制庆大霉素、粘菌素、万古霉素或顺铂诱导的肾毒性。西司他丁可能是一个有前途的药物抑制各种形式的药物诱导的肾毒性介导的megalin在临床设置。
Nephrotoxicity induced by antimicrobial or anticancer drugs is a serious clinical problem. Megalin, an endocytic receptor expressed at the apical membranes of proximal tubules, mediates the nephrotoxicity of aminoglycosides and colistin, key antimicrobials for multidrug-resistant organisms. The mechanisms underlying the nephrotoxicity induced by vancomycin, an antimicrobial for methicillin-resistant Staphylococcus aureus, and cisplatin, an important anticancer drug, are unknown, although the nephrotoxicity of these drugs and gentamicin, an aminoglycoside, is suppressed experimentally with cilastatin. In the clinical setting, cilastatin has been used safely to suppress dehydropeptidase-I-mediated renal metabolism of imipenem, a carbapenem antimicrobial, and thereby limit tubular injury. Here, we tested the hypothesis that cilastatin also blocks megalin-mediated uptake of vancomycin, cisplatin, colistin, and aminoglycosides, thereby limiting the nephrotoxicity of these drugs. Quartz crystal microbalance analysis showed that megalin also binds vancomycin and cisplatin and that cilastatin competes with megalin for binding to gentamicin, colistin, vancomycin, and cisplatin. In kidney specific mosaic megalin knockout mice treated with colistin, vancomycin, or cisplatin, the megalin-replete proximal tubule epithelial cells exhibited signs of injury, whereas the megalin-deficient cells did not. Furthermore, concomitant cilastatin administration suppressed colistin-induced nephrotoxicity in C57BL/6J mice. Notably, cilastatin did not inhibit the antibacterial activity of gentamicin, colistin, or vancomycin in vitro, just as cilastatin did not affect the anticancer activity of cisplatin in previous studies. In conclusion, megalin blockade with cilastatin efficiently suppresses the nephrotoxicity induced by gentamicin, colistin, vancomycin, or cisplatin. Cilastatin may be a promising agent for inhibiting various forms of drug-induced nephrotoxicity mediated via megalin in the clinical setting.