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 associated with the production of nitric oxide (NO), which can initiate apoptotic/necrotic cell death. We studied the role of the p42/44 mitogen-activated protein kinases (MAPKs) and c-Jun N-terminal kinases1/2 (JNK1/2) in NO-evoked cytotoxicity in rat mesangial cells (MC). The NO donor S-nitrosoglutathione time- and concentration-dependently promoted apoptotic cell death as detected by JNK1/2 and caspase-3 activation as well as DNA fragmentation. By using Ro 318220, a JNK1/2 activator, we established a correlation between apoptosis and JNK1/2 activation. Apoptosis is antagonized by the addition of fetal calf serum or the simultaneous generation of NO and superoxide (O(2)(-)), another biological inflammatory mediator. Fetal calf serum-induced protection required p42/44 MAPK activation as inhibition of the p42/44 MAPK pathway by the MAPK kinase-1 inhibitor PD 98059 attenuated MC protection. In contrast, cytoprotection by NO/O(2)(-) cogeneration demanded reduced glutathione 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 against NO-induced JNK1/2 activation and apoptosis in rat MC.