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.
Sandau
K B
KB
University of Erlangen-Nürnberg, Faculty of Medicine, Department of Medicine IV, Experimental Division, Erlangen, Germany.
Callsen
D
D
Brüne
B
B
D000818:Animals; D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D005978:Glutathione / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases; D009569:Nitric Oxide / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D013997:Time Factors
D004791:Enzyme Inhibitors; D007211:Indoles; D009569:Nitric Oxide; D011494:Protein Kinases; D048056:Mitogen-Activated Protein Kinase 9; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione; D010100:Oxygen; C064758:Ro 31-8220