{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T19:17:43Z","timestamp":1789759063682,"version":"4.0.1"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2017,6]]},"abstract":"\n 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\n Staphylococcus aureus<\/jats:italic>\n , 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\u2013mediated 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\n in vitro<\/jats:italic>\n , 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\n via<\/jats:italic>\n megalin in the clinical setting.\n <\/jats:p>","DOI":"10.1681\/asn.2016060606","type":"journal-article","created":{"date-parts":[[2017,1,4]],"date-time":"2017-01-04T21:30:39Z","timestamp":1483565439000},"page":"1783-1791","source":"Crossref","is-referenced-by-count":141,"title":["Megalin Blockade with Cilastatin Suppresses Drug-Induced Nephrotoxicity"],"prefix":"10.1681","volume":"28","author":[{"given":"Yoshihisa","family":"Hori","sequence":"first","affiliation":[{"name":"Respiratory Medicine and Infectious Diseases,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobumasa","family":"Aoki","sequence":"additional","affiliation":[{"name":"Respiratory Medicine and Infectious Diseases,"},{"name":"Advanced Disaster Medical and Emergency Critical Care Center and Intensive Care Units and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoji","family":"Kuwahara","sequence":"additional","affiliation":[{"name":"Applied Molecular Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michihiro","family":"Hosojima","sequence":"additional","affiliation":[{"name":"Clinical Nutrition Science, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryohei","family":"Kaseda","sequence":"additional","affiliation":[{"name":"Clinical Nutrition Science, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sawako","family":"Goto","sequence":"additional","affiliation":[{"name":"Applied Molecular Medicine,"},{"name":"Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomomichi","family":"Iida","sequence":"additional","affiliation":[{"name":"Applied Molecular 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