Megalin deficiency offers protection from renal aminoglycoside accumulation.
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.
Schmitz
Christian
C
Max-Delbrueck-Center for Molecular Medicine, Berlin D-13125, Germany.
Hilpert
Jan
J
Jacobsen
Christian
C
Boensch
Christian
C
Christensen
Erik Ilsø
EI
Luft
Friedrich C
FC
Willnow
Thomas E
TE
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
D000900:Anti-Bacterial Agents; D005839:Gentamicins; D026561:Low Density Lipoprotein Receptor-Related Protein-2