Protection against nitric oxide-induced apoptosis in rat mesangial cells demands mitogen-activated protein kinases and reduced glutathione

Inflammatory diseases such as proliferative glomerulonephritis are associat ed with the production of nitric oxide (NO), which can initiate apoptotic/n ecrotic cell death. We studied the role of the p42/44 mitogen-activated pro tein kinases (MAPKs) and c-Jun N-terminal kinases 1/2 (JNK1/2) in NO-evoked cytotoxicity in rat mesangial cells (MC). The NO donor S-nitrosoglutathion e time- and concentration-dependently promoted apoptotic cell death as dete cted by JNK1/2 and caspase-3 activation as well as DNA fragmentation. By us ing Ro 318220, a JNK1/2 activator, we established a correlation between apo ptosis and JNK1/2 activation. Apoptosis is antagonized by the addition of f etal calf serum or the simultaneous generation of NO and superoxide (O-2(-) ), another biological inflammatory mediator. Fetal calf serum-induced prote ction required p42/44 MAPK activation as inhibition of the p42/44 MAPK path way by the MAPK kinase-1 inhibitor PD 98059 attenuated MC protection. In co ntrast, cytoprotection by NO/O-2(-) cogeneration demanded reduced glutathio ne but was p42/44 MAPK unrelated. Depletion of glutathione reversed NO/O-2( -)-evoked survival to cell destruction and reinstalled JNK1/2 activity. In conclusion, different signal transduction pathways facilitate protection ag ainst NO-induced JNK1/2 activation and apoptosis in rat MC.