Abstract
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 (O2−), 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/O2− cogeneration demanded reduced glutathione but was p42/44 MAPK unrelated. Depletion of glutathione reversed NO/O2−-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.
Footnotes
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Send reprint requests to: Dr. Bernhard Brüne, University of Erlangen-Nürnberg, Faculty of Medicine, Loschgestrasse 8, D-91054 Erlangen, Germany. E-mail:mfm423{at}rzmail.uni-erlangen.de
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↵1 These authors contributed equally to this work.
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This work was supported by the Deutsche Forschungsgemeinschaft (Br 999/8-1 and SFB 423, A5) and the European Community.
- Abbreviations:
- MC
- mesangial cells
- GSNO
- S-nitrosoglutathione
- DMNQ
- 2,3-dimethoxy-1,4-naphtoquinone
- IGF
- insulin growth factor
- DTT
- dithiothreitol
- NO
- nitric oxide
- O2−
- superoxide
- JNK1/2
- c-Jun N-terminal kinases1/2
- MAPK
- mitogen-activated protein kinases
- BSO
- l-buthionine-sulfoxamine
- LDH
- lactate dehydrogenase
- GSH
- glutathione
- MKP-1
- mitogen-activated protein kinase phosphatase-1
- GF
- growth factor
- MEK
- mitogen-activated protein kinase kinase
- DEVD
- N-Acetyl-Asp-Glu-Val-Asp-7
- AMC
- amino-4-methylcoumarin
- Received June 7, 1999.
- Accepted July 14, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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