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Interactions between renal brush border membranes and polyamines
Abstract:
Aminoglycosides are cationic polyamines which accumulate in renal cortex and cause functional as well as structural tubular lesions. To examine the characteristics of aminoglycoside interaction with the kidney brush border membrane, we have measured the aggregation of isolated membranes induced by clinically achievable concentrations of gentamicin and netilmicin. In this assay, competition was observed between the aminoglycoside and other drugs which share the property of inducing a phospholipidosis of lysosomes or displacing Ca++ from anionic phospholipids. Competition for aggregation was demonstrated also between gentamicin and spermine which is a native polyamine product of cell metabolism. Additional data supporting a direct effect of the aminoglycosides on membrane structure came from fluorescence analysis utilizing 8-anilino-1-naphthalene sulfonic acid. Concentrations of gentamicin well below therapeutic levels enhanced the fluorescence intensity of 8-anilino-1-naphthalene sulfonic acid several-fold as did low concentrations of Ca++ and Mg++. The effects of gentamicin and Ca++ on 8-anilino-1-naphthalene sulfonic acid fluorescence were additive. These results indicate that membrane characteristics may be modified by the interaction of native polyamines or subtoxic levels of extrinsic polycations with intrinsic anions on the renal cell surface. The physiologic consequences of these changes warrant further study.
Insights
Aminoglycosides like gentamicin can alter kidney cell membranes by binding to anionic phospholipids. This interaction, even at low doses, affects membrane structure and function, potentially explaining kidney damage.
Area of Science:
- Nephrology
- Biochemistry
- Pharmacology
Background:
- Aminoglycosides accumulate in the renal cortex, causing tubular damage.
- The precise mechanism of aminoglycoside-induced nephrotoxicity at the membrane level requires further elucidation.
Purpose of the Study:
- To investigate the interaction characteristics between aminoglycosides and kidney brush border membranes.
- To understand how aminoglycosides affect membrane structure and function.
Main Methods:
- Assay of isolated kidney brush border membrane aggregation induced by gentamicin and netilmicin.
- Fluorescence analysis using 8-anilino-1-naphthalene sulfonic acid to assess membrane changes.
- Competition assays with other drugs and spermine to identify interaction sites.
Main Results:
- Aminoglycosides induced aggregation of isolated kidney brush border membranes.
- Competition observed between aminoglycosides and Ca++ or drugs causing phospholipidosis.
- Gentamicin, even at sub-therapeutic levels, enhanced 8-anilino-1-naphthalene sulfonic acid fluorescence, indicating membrane perturbation.
- Effects of gentamicin and Ca++ on fluorescence were additive.
Conclusions:
- Aminoglycosides directly interact with and modify kidney brush border membrane structure.
- These interactions involve anionic phospholipids and may be influenced by native polyamines.
- Subtoxic levels of aminoglycosides can alter membrane characteristics, warranting further investigation into physiological consequences.