Mechanism of cisplatin nephrotoxicity in rat renal proximal tubule suspensions

The effect of the nephrotoxic antineoplastic agent, cisplatin, on isolated rat renal proximal tubule suspensions was examined. [(195m)Pt]Cisplatin (31.7 mum) uptake was progressive over a 5-hr incubation period to a maximum value of 8.39 nmol/mg protein. The addition of the metabolic inhibitors KCN and iodoacetic acid reduced cisplatin uptake at the later time points. The organic cation tetraethylammonium (1 mm) reduced [(195m)Pt]cisplatin (31.7 mum) uptake to a greater extent than the organic anion p-aminohippuric acid (1 mm) suggesting preferential use of the cationic transport system by cisplatin. Biochemical perturbations observed included increased release of the lysosomal enzyme N-acetyl-beta-d-glucosaminidase as well as a time- and concentration-dependent increase in lipid peroxidation. Cisplatin inhibited both nystatin-stimulated and ouabain-sensitive respiration (Qo(2)) after only 15 min of treatment. The biochemical changes observed were correlated with morphological alterations in the mitochondria. The results suggest that inhibition of oxidative phosphorylation may be a primary event in cisplatin-induced nephrotoxicity with later changes in lipid peroxidation and enzyme leakage.