Hori Yoshihisa, Aoki Nobumasa, Kuwahara Shoji, Hosojima Michihiro, Kaseda Ryohei, Goto Sawako, Iida Tomomichi, De Shankhajit, Kabasawa Hideyuki, Kaneko Reika, Aoki Hiroyuki, Tanabe Yoshinari, Kagamu Hiroshi, Narita Ichiei, Kikuchi Toshiaki, Saito Akihiko
Departments of Respiratory Medicine and Infectious Diseases.
Advanced Disaster Medical and Emergency Critical Care Center and Intensive Care Units and.
J Am Soc Nephrol. 2017 Jun;28(6):1783-1791. doi: 10.1681/ASN.2016060606. Epub 2017 Jan 4.
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 , 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 , 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 megalin in the clinical setting.
抗菌药物或抗癌药物引起的肾毒性是一个严重的临床问题。巨蛋白是一种在内近端小管顶端膜表达的内吞受体，介导氨基糖苷类药物和黏菌素的肾毒性，这两种药物是治疗多重耐药菌的关键抗菌药物。万古霉素（一种用于耐甲氧西林菌的抗菌药物）和顺铂（一种重要的抗癌药物）引起肾毒性的潜在机制尚不清楚，尽管这些药物和氨基糖苷类药物庆大霉素的肾毒性在实验中可被西司他丁抑制。在临床环境中，西司他丁已被安全地用于抑制脱氢肽酶-I介导的碳青霉烯类抗菌药物亚胺培南的肾脏代谢，从而限制肾小管损伤。在此，我们检验了这样一个假设，即西司他丁也能阻断巨蛋白介导的万古霉素、顺铂、黏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。石英晶体微天平分析表明，巨蛋白也能结合万古霉素和顺铂，且西司他丁与巨蛋白竞争结合庆大霉素、黏菌素、万古霉素和顺铂。在用黏菌素、万古霉素或顺铂治疗的肾脏特异性镶嵌巨蛋白敲除小鼠中，富含巨蛋白的近端小管上皮细胞出现损伤迹象，而缺乏巨蛋白的细胞则未出现。此外，同时给予西司他丁可抑制C57BL/6J小鼠中黏菌素诱导的肾毒性。值得注意的是，西司他丁并不抑制庆大霉素、黏菌素或万古霉素的抗菌活性，正如在先前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能有效抑制庆大霉素、黏菌素、万古霉素或顺铂诱导的肾毒性。在临床环境中，西司他丁可能是一种有前景的药物，用于抑制由巨蛋白介导的各种形式的药物性肾毒性。
