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

Todd, John H.; Sens, Donald A.; Hazen‐Martin, Debra J.; Bylander, John E.; Smyth, Brendan; Sens, Mary Ann

doi:10.1177/019262339202000408

Cited by 9 publications

(5 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The results of this determination demonstrated that the reduction in RT was mediated equally through either apical or basolateral exposure to gentamicin. In contrast to these findings, a previous study by this laboratory that demonstrated the reduction of another electrical parameter, Isc, for these identical HPT cell isolates exposed to gentamicin (25) was selectively mediated by basolateral exposure. The ability to separate apical and basolateral exposure is an important property of the HPT cell system because the apical and basolateral contributions to aminoglycoside nephrotoxicity have not been fully defined.…”

Section: Efect Of Geiitainicin On the Distribution Of Impscontrasting

confidence: 90%

“…The results of this determination demonstrated that exposure to gentamicin, at levels below that producing cell necrosis, caused a marked reduction in Isc and that this reduction followed the known in vivo nephrotoxicities of the aminoglycosides: streptomycin, gentamicin, and neomycin (25). It was further determined that this alteration in electrogenic transport by gentamicin was mediated through exposure of the drug to the basolateral cell surface.…”

Section: Introductionmentioning

confidence: 85%

“…In a previous study, 3 isolates of HPT cells were used to define the effective concentration range of aminoglycoside exposure for cells grown on permeable supports (25). These identical isolates were used in the present study to determine whether or not the RT of HPT cell monolayers was affected by exposure to aminoglycosides known to have varying in vivo toxicity.…”

Section: Amiiioglycosides Of Varying Toxicitymentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 1994

Self Cite

View full text Add to dashboard Cite

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 (R,) 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 freezefracture analysis demonstrated only minimal alteration of the sealing strands as a result of aminoglycoside exposure. Consequently, the reductions in R, 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.

show abstract

Section: Efect Of Geiitainicin On the Distribution Of Impscontrasting

confidence: 90%

Section: Introductionmentioning

confidence: 85%

Section: Amiiioglycosides Of Varying Toxicitymentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 1994

Self Cite

View full text Add to dashboard Cite

show abstract

“…In experiments carried out with cultured cells or membrane vesicles from tubular cells, it has been shown that gentamicin, independently of cell injury, inhibits a variety of cell membrane transporters of both the brush-border and the basolateral membrane (reviewed in Mingeot-Leclercq and Tulkens 20 ) including (i) Na-Pi cotransporter 73 and Na-H exchange; 74 (ii) carrier-mediated dipeptide transport; 75 (iii) electrogenic Na transport; 76 and (iv) Na-K adenosine triphosphatase. 77,78 Transport inhibition affects tubular reabsorption, but it may also compromise cell viability ( Figure 1).…”

Section: Sub-lethal Alterations In Tubular Reabsorptionmentioning

confidence: 99%

New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view

Quirós

Vicente

et al. 2011

Kidney International

581

421

View full text Add to dashboard Cite

Nephrotoxicity is one of the most important side effects and therapeutical limitations of aminoglycoside antibiotics, especially gentamicin. Despite rigorous patient monitoring, nephrotoxicity appears in 10-25% of therapeutic courses. Traditionally, aminoglycoside nephrotoxicity has been considered to result mainly from tubular damage. Both lethal and sub-lethal alterations in tubular cells handicap reabsorption and, in severe cases, may lead to a significant tubular obstruction. However, a reduced glomerular filtration is necessary to explain the symptoms of the disease. Reduced filtration is not solely the result of tubular obstruction and tubular malfunction, resulting in tubuloglomerular feedback activation; renal vasoconstriction and mesangial contraction are also crucial to fully explain aminoglycoside nephrotoxicity. This review critically presents an integrative view on the interactions of tubular, glomerular, and vascular effects of gentamicin, in the context of the most recent information available. Moreover, it discusses therapeutic perspectives for prevention of aminoglycoside nephrotoxicity derived from the pathophysiological knowledge.

show abstract

“…38 Culture of these cells on semi-permeable membranes also allows membrane-specific exposure of the cells to chemicals, which can provide valuable mechanistic data and is essential if the compound is known to be transported specifically by the basolateral membrane, which would otherwise be in contact with the tissue culture plate. Several of the cell lines of proximal tubular origin which are available are deficient in one or more proximal tubular functions; for example, the widely used LLC PK, cell line does not exhibit the anion transport system, which is implicated in the proximal tubular toxicity of such drugs as the cephalosporins.…”

Section: Cryopreservation Of Human Hepatocytesmentioning

confidence: 99%

Advantages and Disadvantages of Using Human Cells for Pharmacological and Toxicological Studies

Hawksworth

1994

Hum Exp Toxicol

View full text Add to dashboard Cite

1 Marked species differences in the distribution and affinity of drug receptors, and in the patterns of biotransformation and susceptibility to the toxicity of xenobiotics, provide the impetus for using human tissues for pharmacological and toxicological studies. 2 Studies with intact cells facilitate the correlation of xenobiotic metabolism with cellular indices of toxicity, which can provide the mechanistic basis for understanding species differences in toxicity. 3 Human cells in suspension or primary culture reflect the variability in susceptibility to toxicity in a population. 4 The current limitation to these studies is scarcity of human material, the need for improved (cryo)preservation techniques for human hepatocytes/precision-cut slices and difficulties in predicting in vivo exposure-risk relationships from in vitro dose-response relationships.

show abstract

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

Cited by 9 publications

References 27 publications

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

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

New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view

Advantages and Disadvantages of Using Human Cells for Pharmacological and Toxicological Studies

Contact Info

Product

Resources

About