title: Megalin deficiency offers protection from renal aminoglycoside accumulation.
abstract: 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.
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, Berlin D-13125, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schmitz
authors.forename: Jan
authors.initials: J
authors.lastname: Hilpert
authors.forename: Christian
authors.initials: C
authors.lastname: Jacobsen
authors.forename: Christian
authors.initials: C
authors.lastname: Boensch
authors.forename: Erik Ilsø
authors.initials: EI
authors.lastname: Christensen
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000633:toxicity; D005839:Gentamicins / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D026561:Low Density Lipoprotein Receptor-Related Protein-2