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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.
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