Gentamicin inhibits rat renal cortical homotypic endosomal fusion:
role of megalin.
Hammond, Timothy G., Rebecca R. Majewski, James H. Kaysen, Fatima O.
Goda, Gabriel L. Navar, Francoise Pontillon, and Pierre J. Verroust.
Tulane University School of Medicine, & New Orleans Veteran's
Affairs Medical Center, New Orleans LA, University of Wisconsin
Hospital and Clinics, & William S. Middleton Memorial V.A.
Hospital, Madison WI USA and Unite de Recherches de Nephrologie
Normale and Pathologique, INSERM U.64 Hopital Tenon Paris CEDEX 20
France
APStracts 3:0184F, 1996.
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, and if 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 did
inhibit fusion, whereas non-specific controls had no effect. Peptides
matching homologous NPXY repeat sequence motifs in the cytosolic tail
stimulated endosomal fusion, while 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.
Received 25 October 1995; accepted in final form 19 September
1996.
APS Manuscript Number F363-5.
Article publication pending Am. J. Physiol. (Renal Fluid Electrolyte
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 5 November 1996