Aminoglycoside antibiotics alter the electrogenic transport properties of cultured human proximal tubule cells.
Monolayers of human proximal tubule (HPT) cells, when grown on permeable supports and mounted in Ussing chambers, spontaneously display a transepithelial potential difference (PD) and short-circuit current (Isc). These electrical parameters were used in the present study to determine if aminoglycoside exposure altered electrogenic sodium transport by HPT cells. 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. It was concluded through a similar analysis on a total of 14 isolates of HPT cells that the aminoglycosides repeatably reduced the electrogenic sodium transport of HPT cells. It was further determined that this alteration in electrogenic transport by gentamicin was mediated through exposure of the drug to the basolateral cell surface and that apical exposure had little effect. Evidence was obtained against the involvement of Na+, K(+)-ATPase, adenosine 3',5'-cyclic monophosphate, and sodium-coupled substrate transport in this alteration in electrogenic transport by the aminoglycosides. The basolaterally located Na+: CO3(-2):HCO3(-1) symporter is a possible site for aminoglycoside-induced nephrotoxicity.
Todd
J H
JH
Department of Pathology, Medical University of South Carolina, Charleston 29425.
Sens
D A
DA
Hazen-Martin
D J
DJ
Bylander
J E
JE
Smyth
B J
BJ
Sens
M A
MA
D000328:Adult; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002675:Child, Preschool; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004594:Electrophysiology; D005260:Female; D005839:Gentamicins / Q000633:toxicity*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008875:Middle Aged; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013268:Stimulation, Chemical
D000900:Anti-Bacterial Agents; D005839:Gentamicins; D005576:Colforsin; D012964:Sodium; D000242:Cyclic AMP; D000254:Sodium-Potassium-Exchanging ATPase