Effects of gentamicin on the renal uptake of endogenous and exogenous protein in conscious rats

Abstract

To study the effect of gentamicin on the renal uptake of proteins, Sprague-Dawley female rats were intravenously injected with solutions containing unlabeled human beta 2-microglobulin (beta 2-m), retinol-binding protein, and increasing amounts of gentamicin (from 0.063 up to 31.5 mg/kg). The concentrations of human proteins and that of endogenous beta 2-m, albumin, and IgG in the urine collected during the 2 hr following the injection were determined by immunoassays. Gentamicin transiently increased the urinary excretion of rat and human beta 2-m in a dose-dependent manner. The mean relative increase of rat beta 2-m excretion ranged from 2 at a gentamicin dose of 0.06 mg/kg up to 500 at a gentamicin dose of 31.5 mg/kg. By contrast, the urinary excretion of other proteins was only increased by a factor of 2 to 5 at the highest dose of gentamicin. The relative increase of the urinary excretion of proteins was positively correlated with the fractional reabsorption of the proteins by the rat kidney. The inhibitory effect of gentamicin on the renal uptake of protein was very similar to that observed in rats injected with polycationic proteins like lysozyme and cytochrome C. These observations, combined with the fact that gentamicin, like proteins, enters the tubular cell by adsorptive endocytosis, strongly suggest that this drug competes with proteins for common binding sites on the apical tubular membrane and for subsequent endocytosis. Furthermore, the iv injection of large amounts of gentamicin and polycationic proteins induces a lysosomal enzymuria which very likely is a manifestation of an increased exocytosis.