title: Megalin Blockade with Cilastatin Suppresses Drug-Induced Nephrotoxicity.
abstract: 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-resistantStaphylococcus 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 vancomycinin 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 mediatedviamegalin in the clinical setting.
authors.affiliation: Departments of Respiratory Medicine and Infectious Diseases.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Hori
authors.affiliation: Departments of Respiratory Medicine and Infectious Diseases.|Advanced Disaster Medical and Emergency Critical Care Center and Intensive Care Units and.
authors.forename: Nobumasa
authors.initials: N
authors.lastname: Aoki
authors.affiliation: Applied Molecular Medicine.
authors.forename: Shoji
authors.initials: S
authors.lastname: Kuwahara
authors.affiliation: Clinical Nutrition Science, and.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Hosojima
authors.affiliation: Clinical Nutrition Science, and.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Kaseda
authors.affiliation: Applied Molecular Medicine.|Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Sawako
authors.initials: S
authors.lastname: Goto
authors.affiliation: Applied Molecular Medicine.|Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Tomomichi
authors.initials: T
authors.lastname: Iida
authors.affiliation: Applied Molecular Medicine.|Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Shankhajit
authors.initials: S
authors.lastname: De
authors.affiliation: Clinical Nutrition Science, and.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kabasawa
authors.affiliation: Applied Molecular Medicine.
authors.forename: Reika
authors.initials: R
authors.lastname: Kaneko
authors.affiliation: Applied Molecular Medicine.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aoki
authors.affiliation: Division of Infection Control and Prevention, Niigata University Medical and Dental Hospital, Niigata, Japan; and.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Tanabe
authors.affiliation: Division of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka-shi, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kagamu
authors.affiliation: Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Ichiei
authors.initials: I
authors.lastname: Narita
authors.affiliation: Departments of Respiratory Medicine and Infectious Diseases.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: Applied Molecular Medicine, akisaito@med.niigata-u.ac.jp.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Saito
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D015377:Cilastatin / Q000494:pharmacology* / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000188:drug therapy*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D015377:Cilastatin
keywords: Colistin; Vancomycin; cisplatin; gentamicin; nephrotoxicity