Effect of Cadmium on Organic Acid Transport System in Renal Basolateral Membrane

Effect of Cadmium on Organic Acid Transport System in Renal Basolateral Membrane

Chronic exposure to cadmium impairs various renal tubular functions, including organic acid (anion) secretion. To investigate the mechanism of cadmium-induced alterations in the organic anion transport system, kinetics of p-aminohippurate (PAH) uptake was studied in renal cortical basolateral membrane vesicles (BLMV) isolated from cadmium-intoxicated rats (adult male Sprague-Dawley). Cadmium intoxication was induced by subcutaneous injections of CdCl₂ (2 mg Cd/kg per day) for 3 weeks. The renal plasma membrane vesicles were prepared by Percoll gradient centrifugation. The vesicular uptake of ¹⁴C-PAH was determined by rapid filtration technique using Millipore filter. Cadmium intoxication resulted in a marked attenuation of Na⁺-dependent, α-ketoglutarate (αKG)-driven PAH uptake with no changes in Na⁺ and αKG-independent transport component. Kinetic analysis indicated that Vmax, but not Km, of the Na⁺-dependent, αKG-driven component was reduced. A similar reduction of Na⁺-dependent, αKG-driven PAH uptake was observed in normal membrane vesicles directly exposed to inorganic cadmium in vitro, and this was accompanied by an inhibition of both Na⁺-dependent αKG uptake and αKG-PAH exchange activity. These results indicate that during chronic exposure to cadmium, free cadmium ions liberated in the proximal tubular cytoplasm directly interact with the basolateral membrane and impair the active transport capacity for organic anions, most likely due to an inhibition of both Na⁺-dicarboxylate cotransporter and dicarboxylate-organic anion antiporter activities.