Targeted prevention of renal accumulation and toxicity of gentamicin by aminoglycoside binding receptor antagonists.
Receptor-mediated endocytosis plays an important role in accumulation of aminoglycosides in renal proximal tubule. To prevent aminoglycoside-induced nephrotoxicity following concentrated accumulation of gentamicin in the kidney, effect of cationic proteins and their peptide fragments, which could inhibit gentamicin binding to its binding receptor(s), was investigated. Among several substrates for megalin, an endocytic receptor responsible for renal accumulation of aminoglycosides, cytochrome c potently inhibited gentamicin accumulation in renal cortex. Concentration-dependent inhibition by cytochrome c on gentamicin uptake was also observed in OK kidney epithelial cells expressing megalin. In addition, gentamicin-induced increase in urinary excretion of N-acetyl-beta-d-glucosaminidase (NAG), a marker of renal tubular damage, was significantly reduced by cytochrome c. We next attempted to find a peptide fragment with lower molecular size showing inhibitory effect on gentamicin uptake. Cyto79-88 inhibited gentamicin uptake in OK cells, but had little effect on renal accumulation of gentamicin in mice in vivo. On one hand, a peptide fragment of neural Wiskott-Aldrich syndrome protein (N-WASP), which interacts with acidic phospholipids like aminoglycosides, inhibited gentamicin accumulation not only in OK cells but also in mouse kidney. These results show that substrates and/or their peptide fragments for aminoglycoside binding receptor such as megalin might be useful for preventing aminoglycoside-induced nephrotoxicity.
Watanabe
Ayahisa
A
Department of Pharmaceutics and Therapeutics, Division of Clinical Pharmaceutical Science, Programs for Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Nagai
Junya
J
Adachi
Yoshinori
Y
Katsube
Takayuki
T
Kitahara
Yasumi
Y
Murakami
Teruo
T
Takano
Mikihisa
M
D000118:Acetylglucosaminidase / Q000037:antagonists & inhibitors / Q000652:urine; D000617:Aminoglycosides / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D007611:Aprotinin / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D002478:Cells, Cultured; D045304:Cytochromes c / Q000737:chemistry / Q000494:pharmacology; D003681:Dehydration / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004359:Drug Therapy, Combination; D004705:Endocytosis / Q000187:drug effects; D005839:Gentamicins / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000097:blood; D007564:Japan; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000008:administration & dosage / Q000737:chemistry / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009113:Muramidase / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000627:therapeutic use*; D013045:Species Specificity; D014018:Tissue Distribution / Q000187:drug effects; D014316:Tritium
D000617:Aminoglycosides; D005839:Gentamicins; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010455:Peptides; D011955:Receptors, Drug; C495115:cyto79-88; D014316:Tritium; D045304:Cytochromes c; D007611:Aprotinin; D009113:Muramidase; D000118:Acetylglucosaminidase