Inhibition of intrinsic and extrinsic pathway-mediated apoptosis by cadmium.

摘要

Cadmium (Cd) is a toxic metal that has been shown to induce apoptosis in some cells and inhibit apoptosis in others. In the present study using human mesangial cells, 10 muM Cd2+ inhibited DNA laddering and caspase-9 activity induced by serum withdrawal. DNA laddering, caspase activation, and nuclear fragmentation induced by 50 ng/ml TNF-alpha plus the p38 MAP kinase inhibitor SB203580 (2 muM) was also inhibited by 10 muM Cd2+ as was DNA laddering and caspase activation induced by 25 muM camptothecin, a topoisomerase I inhibitor. The inhibition of DNA laddering was specific to Cd2+ compared with other metal cations including Zn2+ and Hg2+. Furthermore, 10 muM Cd2+ prevented cytochrome c release. We conclude that Cd2+ inhibits apoptosis in mesangial cells by inhibiting the caspases at multiple levels.{09}In addition, procaspase-9 was activated in both the intrinsic (camptothecin) and extrinsic (TNF-alpha/SB203580) apoptotic pathways signifying its importance in mesangial cell apoptosis.