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Gentamicin inhibits rat renal cortical homotypic endosomal fusion: Role of megalin

Publication ,  Journal Article
Hammond, TG; Majewski, RR; Kaysen, JH; Goda, FO; Navar, GL; Pontillon, F; Verroust, PJ
Published in: American Journal of Physiology
December 1, 1997

-Megalin, a giant glycoprotein receptor heavily concen-trated 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 nonspecific 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.

Duke Scholars

Published In

American Journal of Physiology

ISSN

0002-9513

Publication Date

December 1, 1997

Volume

272

Issue

1 PART 2

Related Subject Headings

  • Cardiovascular System & Hematology
 

Citation

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Hammond, T. G., Majewski, R. R., Kaysen, J. H., Goda, F. O., Navar, G. L., Pontillon, F., & Verroust, P. J. (1997). Gentamicin inhibits rat renal cortical homotypic endosomal fusion: Role of megalin. American Journal of Physiology, 272(1 PART 2).
Hammond, T. G., R. R. Majewski, J. H. Kaysen, F. O. Goda, G. L. Navar, F. Pontillon, and P. J. Verroust. “Gentamicin inhibits rat renal cortical homotypic endosomal fusion: Role of megalin.” American Journal of Physiology 272, no. 1 PART 2 (December 1, 1997).
Hammond TG, Majewski RR, Kaysen JH, Goda FO, Navar GL, Pontillon F, et al. Gentamicin inhibits rat renal cortical homotypic endosomal fusion: Role of megalin. American Journal of Physiology. 1997 Dec 1;272(1 PART 2).
Hammond, T. G., et al. “Gentamicin inhibits rat renal cortical homotypic endosomal fusion: Role of megalin.” American Journal of Physiology, vol. 272, no. 1 PART 2, Dec. 1997.
Hammond TG, Majewski RR, Kaysen JH, Goda FO, Navar GL, Pontillon F, Verroust PJ. Gentamicin inhibits rat renal cortical homotypic endosomal fusion: Role of megalin. American Journal of Physiology. 1997 Dec 1;272(1 PART 2).

Published In

American Journal of Physiology

ISSN

0002-9513

Publication Date

December 1, 1997

Volume

272

Issue

1 PART 2

Related Subject Headings

  • Cardiovascular System & Hematology