Effects of extracellular cadmium on renal basolateral organic anion transport.
Heavy metal ions are well-known nephrotoxic agents. Usually, they induce a damage of various renal transport systems. Cd2+, however, has been shown to enhance renal basolateral organic cation transport. Therefore, the effects of Cd2+ on the basolateral p-aminohippuric acid (PAH) uptake of microdissected nonperfused rabbit kidney S2 proximal tubule segments were investigated. Incubation with Cd2+ induced a bell-shaped concentration response curve with a 2-fold increase of the PAH transport at a Cd2+ concentration of 10(-6) M. Since Cd2+ has been described to activate protein kinase C (PKC), the effects of the PKC inhibitor staurosporine were also tested. Staurosporine (10(-8) M) could, however, not reduce the effects of Cd2+. Cd2+ may exert its effects by an as yet unknown mechanism that is different from the PKC-activating mechanism of phorbol esters. A stimulation of the tricarboxylic acid cycle in kidney cells by Cd2+ may, however, increase the delivery of alpha-ketoglutarate. Indeed, incubation of proximal tubules with alpha-ketoglutarate increased PAH transport across the basolateral membrane significantly. Thus, the observed effects of Cd2+ may be due to an enhanced transport of p-aminohippuric acid by stimulation of exchange of PAH with alpha-ketoglutarate. The modulation of renal organic anion transport may be another aspect of Cd2+ nephrotoxicity.
Hohage
H
H
Medical Department D, University of Münster, Germany. hohage@uni-muenster.de
Mehrens
T
T
Mergelsberg
U
U
Löhr
M
M
Greven
J
J
D000818:Animals; D027321:Anion Transport Proteins; D001485:Basement Membrane / Q000187:drug effects / Q000378:metabolism; D002104:Cadmium / Q000633:toxicity*; D002352:Carrier Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007656:Ketoglutaric Acids / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011817:Rabbits; D019311:Staurosporine / Q000494:pharmacology; D010130:p-Aminohippuric Acid / Q000378:metabolism*
D027321:Anion Transport Proteins; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007656:Ketoglutaric Acids; D002104:Cadmium; D011493:Protein Kinase C; D019311:Staurosporine; D010130:p-Aminohippuric Acid