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Gentamicin inhibits rat renal cortical homotypic endosomal fusion: role of megalin
Ist Teil von
American journal of physiology. Renal physiology, 1997-01, Vol.272 (1), p.117-F123
Ort / Verlag
United States
Erscheinungsjahr
1997
Quelle
MEDLINE
Beschreibungen/Notizen
T. G. Hammond, R. R. Majewski, J. H. Kaysen, F. O. Goda, G. L. Navar, F. Pontillon and P. J. Verroust
Tulane University School of Medicine, New Orelans, Louisiana, USA.
Megalin, a giant glycoprotein receptor heavily concentrated in the early
endosomal pathway of renal proximal tubular cells, binds gentamicin with
high affinity and delivers the drug to lysosomes. Utilizing an in vitro
reconstitution assay we tested whether gentamicin-induced vacuolation is
associated with inhibition of early endosomal fusion, as well as whether
megalin plays a role in mediating these effects. Pretreatment of rats with
gentamicin inhibited rat renal proximal tubular homotypic endosomal fusion.
Administered simultaneously, gentamicin and polymers of polyaspartic acid,
which protect against the hemodynamic effects of gentamicin nephrotoxicity,
had no net effect on fusion. Polyaspartic acid alone had no effect on
fusion. Antisera to the tail of the megalin/gentamicin receptor inhibited
fusion, whereas non-specific controls had no effect. Peptides matching
homologous NPXY repeat sequence motifs in the cytosolic tail stimulated
endosomal fusion, whereas reverse sequence control peptides had no effect.
These data suggest that gentamicin inhibition of endosomal fusion in the
renal proximal tubule is a damage mechanism mediated by specific peptide
sequences in the cytosolic tail of the giant gentamicin-binding receptor
megalin and that receptors can effect the fusion properties of membranes in
which they reside.