Potentiation by nitric oxide of cyclosporin a and FK506-induced apoptosis in renal proximal tubule cells

Proximal tubular epithelial cells (PTEC) exhibit a high sensitivity to unde rgo apoptosis in response to proinflammatory stimuli and immunosuppressors and participate in the onset of several renal diseases. This study examined the expression of inducible nitric oxide (NO) synthase after challenge of PTEC with bacterial cell wall molecules and inflammatory cytokines and anal yzed the pathways that lead to apoptosis in these cells by measuring change s in the mitochondrial transmembrane potential and caspase activation. The data show that the apoptotic effects of proinflammatory stimuli mainly were due to the expression of inducible NO synthase. Cycloslporin A and FK506 i nhibited partially NO synthesis. However, both NO and immunosuppressors ind uced apoptosis, probably through a common mechanism that involved the irrev ersible opening of the mitochondrial permeability transition pore. Activati on of caspases 3 and 7 was observed in cells treated with high doses of NO and with moderate concentrations of immunosuppressors. The conclusion is th at the cooperation between NO and immunosuppressors that induce apoptosis i n PTEC might contribute to the renal toxicity observed in the course of imm unosuppressive therapy.