Aminoglycoside Antibiotics Alter the Paracellular Transport Properties of Cultured Human Proximal Tubule Cells

Abstract

Cell cultures retaining properties of the human proximal tubule were utilized to determine whether or not the aminoglycoside antibiotics alter paracellular transport. The transepithelial resistance (RT) of the human proximal tubule (HPT) cell monolayers was determined by Ussing chamber analysis of cells grown on permeable supports. This analysis revealed that RT was reduced as a result of aminoglycoside exposure and that the reduction corresponded to the known clinical nephrotoxicities of the aminoglycosides. Variation in the aminoglycoside concentration necessary to elicit this response was documented using 14 individual cell isolates. Ultrastructural analysis provided evidence indicating that the alterations in RT were not associated with general damage to the HPT cells. An examination of the structure of the tight junctions by freeze-fracture analysis demonstrated only minimal alteration of the sealing strands as a result of aminoglycoside exposure. Consequently, the reductions in RT were not directly associated with discernible tight junction structural alterations. Alteration in the paracellular route of transport, as indicated by altered RT values, was clearly documented as a result of aminoglycoside exposure. In addition, this alteration was accompanied by an increased density of intramembrane particles within the apical cell membrane.