Renal brush border membrane vesicle aminoglycoside binding and nephrotoxicity

Area of Science:

• Pharmacology
• Toxicology
• Nephrology

Background:

• In vitro binding affinity of aminoglycoside (AG) antibiotics to renal brush border membranes (BBM) correlates with in vivo AG nephrotoxicity in rats.
• Previous studies linked variables like sex, age, and antibiotic type to AG nephrotoxicity.

Purpose of the Study:

• To extend the correlation of in vitro binding affinity to in vivo differences in tobramycin sensitivity between rat strains.
• To investigate gender differences in tobramycin nephrotoxicity by comparing BBM binding affinity.
• To compare tobramycin binding characteristics in rat and human renal BBM.

Main Methods:

• Compared in vitro tobramycin binding affinity (KD) and binding capacities in different rat strains and sexes.
• Utilized renal BBM vesicles from rat kidneys and a single human kidney for binding studies.
• Performed Scatchard analyses to characterize binding kinetics and identified binding sites.
• Assessed the effect of polyaspartic acid on tobramycin binding to human BBM vesicles.

Main Results:

• Tobramycin binding affinity (KD) did not correlate with in vivo strain differences in AG nephrotoxicity.
• BBM vesicle tobramycin binding affinity did not correlate with previously reported in vivo gender differences in tobramycin nephrotoxicity.
• Binding capacities correlated with in vivo nephrotoxicity comparisons only between male Sprague-Dawley and male Fischer rats.
• Tobramycin binding to human renal BBM vesicles showed similar rapid, saturable kinetics and low affinity, high capacity characteristics as rat BBM.
• Polyaspartic acid blocked tobramycin binding to human BBM vesicles.

Conclusions:

• Aminoglycoside binding to renal BBM is qualitatively similar in rats and humans.
• Quantitative kinetic aspects like KD and binding capacities may not be critical determinants in the pathogenesis of AG nephrotoxicity.