Dual pathways for organic anion secretion in renal proximal tubule.
Transport on the "classical" organic anion system in renal proximal tubule is specific, active, Na-dependent, and ouabain sensitive. Here we review recent studies using intact teleost proximal tubules and laser scanning confocal microscopy which show that the secretion of large organic anions, such as, fluorescein-methotrexate (FL-MTX, Mw 923 Da) is handled by a separate and distinct organic anion transport system. In contrast to the classical system, FL-MTX uptake into cells and secretion into the tubular lumen was ouabain insensitive and largely Na-independent. KCN did not affect cellular uptake but abolished secretion into the lumen. PAH and probenecid, potent inhibitors of transport on the classical system, were weak inhibitors of FL-MTX transport. Uptake and secretion of FL-MTX were inhibited by micromolar concentrations of other organic anions (MTX, folate, bromocresol green, bromosulfonphthalein). FL-MTX secretion into the lumen was inhibited by leukotriene C4 and cyclosporine A, neither of which affected transport of the model substrate for the classical system, fluorescein. Thus, FL-MTX secretion is specific, but largely Na-independent and ouabain-insensitive. Both the basolateral and luminal steps in FL-MTX transport differ from those associated with fluorescein and P-aminohippurate secretion.
Miller
D S
DS
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. miller@niehs.nih.gov
Pritchard
J B
JB
D000818:Animals; D001692:Biological Transport; D005399:Fishes / Q000502:physiology; D005452:Fluoresceins / Q000378:metabolism; D016623:Ion Pumps / Q000502:physiology*; D007687:Kidney Tubules, Proximal / Q000502:physiology*; D008727:Methotrexate / Q000378:metabolism; D009930:Organic Chemicals / Q000378:metabolism; D010042:Ouabain / Q000008:administration & dosage
D005452:Fluoresceins; D016623:Ion Pumps; D009930:Organic Chemicals; D010042:Ouabain; D008727:Methotrexate