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.