Dual action of phosphonoformic acid on Na(+)-phosphate cotransport in opossum kidney cells.
Phosphonoformic acid (PFA, foscarnet) was found to exert both an inhibitory and a stimulatory effect on Na(+)-dependent Pi transport in opossum kidney (OK) cells. When added in the uptake media, PFA produced a dose-dependent inhibition of Na(+)-Pi cotransport. PFA had no effect on the Na(+)-dependent transports of methyl-alpha-D-glucopyranoside (AMG) or L-alanine or on amiloride-sensitive Na(+)-H+ antiport. The inhibition of Na(+)-Pi cotransport was competitive [inhibitory constant (Ki) = 6.0 mM], reversible by dilution, and solute specific. When OK cells were incubated with PFA for longer time periods (1-15 h), the Na(+)-Pi uptake measured after removal of PFA was significantly increased, i.e., "upregulated." The extent of Na(+)-Pi cotransport upregulation was dependent on time (greater than or equal to 30 min) and dose of PFA (2-10 mM). The increase in Na(+)-Pi cotransport by upregulation with PFA was due to higher apparent Vmax with no change in apparent Michaelis constant (Km) for Pi and was solute specific: uptakes of AMG or L-proline were not changed. Removal of PFA from culture medium resulted in a fast reversal of upregulation. Upregulation was not inhibited by cycloheximide, actinomycin D, or cordycepin. Solute-specific increase of Na(+)-Pi cotransport was also found when measured in apical membrane vesicles isolated from OK cells. Thus PFA exerts a dual action on the Na(+)-Pi cotransporter of OK cells: 1) acute, competitive inhibition and 2) after prolonged exposure it increases Na(+)-Pi uptake, probably by insertion of Na(+)-Pi cotransporters into apical membrane.
Loghman-Adham
M
M
Department of Pediatrics, University of Utah School of Medicine, Salt Lake City 84132.
Dousa
T P
TP
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002264:Carboxylic Acids / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D017245:Foscarnet; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D007700:Kinetics; D009893:Opossums; D063065:Organophosphonates / Q000494:pharmacology; D010710:Phosphates / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D011506:Proteins / Q000037:antagonists & inhibitors; D012313:RNA / Q000037:antagonists & inhibitors; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters; D013997:Time Factors; D015854:Up-Regulation
D002264:Carboxylic Acids; D002352:Carrier Proteins; D063065:Organophosphonates; D010710:Phosphates; D011506:Proteins; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters; D017245:Foscarnet; D012313:RNA; D010746:Phosphonoacetic Acid