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J. Biol. Chem., Vol. 277, Issue 1, 618-622, January 4, 2002
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From the Aminoglycosides are antibiotics commonly used to
treat life-threatening Gram-negative bacterial infections. However,
their use is hampered by their severe nephrotoxicity due to
accumulation in renal proximal tubules. Several pathways have been
implicated in the renal uptake of aminoglycosides including megalin, an
endocytic receptor in proximal tubular cells. Here, we have used mouse
models with genetic or functional megalin deficiency to explore the
contribution of megalin and other pathways to renal aminoglycoside
uptake in vivo. We demonstrate that the uptake of
aminoglycosides into the kidney directly correlates with renal megalin
activity and is completely eliminated in mice lacking the receptor.
Thus, our studies provide unequivocal evidence that megalin is the only major pathway responsible for renal aminoglycoside accumulation and
that the receptor represents a unique drug target to prevent aminoglycoside-induced nephrotoxicity in patients.
Megalin Deficiency Offers Protection from Renal
Aminoglycoside Accumulation*
,,,
, and**
Max-Delbrueck-Center for Molecular
Medicine and ** Medical Faculty of the Free University of
Berlin, Berlin D-13125, Germany, Franz-Volhard-Clinic,
Medical Faculty of the Humboldt University of Berlin, Berlin
D-13125, Germany, and Departments of § Medical Biochemistry
and ¶ Cell Biology, University of Aarhus, DK-8000 Aarhus,
Denmark
*
This work was supported by the Deutsche
Forschungsgemeinschaft, the Verbund Klinische Pharmakologie
Berlin-Brandenburg, the Danish Medical Research Council, the
NOVO-Nordisc Foundation, and the University of Aarhus.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed:
Max-Delbrueck-Center for Molecular Medicine, Robert-Roessle-Strasse 10, D-13125 Berlin, Germany. Tel.: 49-30-9406-2569; Fax: 49-30-9406-3382; E-mail: willnow@mdc-berlin.de.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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