Nitric oxide stimulates stress‐activated protein kinases in glomerular endothelial and mesangial cells

Pfeilschifter, Josef; Huwiler, Andrea

doi:10.1016/0014-5793(96)01070-8

Cited by 56 publications

(35 citation statements)

References 42 publications

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“…These findings are consistent with observations in other cells, where NO donors also induce activation of JNK and p38 and to a lesser extent ERK [38][39][40][41][42][43][44], thus supporting our findings. Further, the NO-donor sodium (Z)-1(N,N-diethylamino) diazen-1-ium-1,2-diolate at 500 μmol/l induced phosphorylation of p38 and JNK1/2 during 10-or 30-min treatments in insulinsecreting rat RINm5F cells [35].…”

Section: Discussionsupporting

confidence: 94%

Nitric oxide contributes to cytokine-induced apoptosis in pancreatic beta cells via potentiation of JNK activity and inhibition of Akt

et al. 2005

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Aims/hypothesis: Pro-inflammatory cytokines cause beta cell secretory dysfunction and apoptosis-a process implicated in the pathogenesis of type 1 diabetes. Cytokines induce the expression of inducible nitric oxide (NO) synthase (iNOS) leading to NO production. NO contributes to cytokine-induced apoptosis, but the underlying mechanisms are unclear. The aim of this study was to investigate whether NO modulates signalling via mitogenactivated protein kinases (MAPKs) and Akt. Materials and methods: MAPK activities in INS-1 cells and isolated islets were determined by immunoblotting and in vitro kinase assay. Apoptosis was determined by ELISA measurement of histone-DNA complexes present in cytoplasm. Results: Apoptosis in INS-1 cells induced by IL-1β plus IFNγ was dependent on NO production as demonstrated by the use of the NOS blocker N G -methyl-Larginine. Accordingly, an NO donor (S-nitroso-N-acetyl-D, L-penicillamine, SNAP) dose-dependently caused apoptosis in INS-1 cells. SNAP activated c-Jun N-terminal kinase (JNK) and p38 MAPK, but suppressed the activity of extracellular signal-regulated kinase MAPK. In rat islets, NOS inhibition decreased JNK and p38 activities induced by a 6-h exposure to IL-1β. Likewise, IL-1β-induced JNK and p38 activities were lower in iNOS (−/−) mouse islets than in wild-type islets. In human islets, SNAP potentiated IL-1β-induced JNK activation. The constitutive level of active, Ser473-phosphorylated Akt in INS-1 cells was suppressed by SNAP. IGF-I activated Akt and protected against SNAP-induced apoptosis. The anti-apoptotic effect of IGF-I was not associated with reduced JNK activation. Conclusions/interpretation: We suggest that NO contributes to cytokine-induced apoptosis via potentiation of JNK activity and suppression of Akt.

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Section: Discussionsupporting

confidence: 94%

Nitric oxide contributes to cytokine-induced apoptosis in pancreatic beta cells via potentiation of JNK activity and inhibition of Akt

et al. 2005

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“…Recently, we and others have demonstrated activation of this MAPK pathway by IL-1␤ and NO in rat MC (17,46,47). The finding that IL-1␤-mediated phosphorylation of JNK is strongly enhanced by O 2 Ϫ indicates that JNK or its upstream activators may function as further targets of O 2 Ϫ action in MC.…”

Section: Discussionmentioning

confidence: 90%

Amplification of IL-1β-Induced Matrix Metalloproteinase-9 Expression by Superoxide in Rat Glomerular Mesangial Cells Is Mediated by Increased Activities of NF-κB and Activating Protein-1 and Involves Activation of the Mitogen-Activated Protein Kinase Pathways

Eberhardt

Huwiler

Beck

et al. 2000

The Journal of Immunology

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175

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The modulation of cell signaling by free radicals is important for the pathogenesis of inflammatory diseases. Recently, we have shown that NO reduces IL-1β-induced matrix metalloproteinase (MMP-9) expression in glomerular mesangial cells (MC). Here we report that exogenously administrated superoxide, generated by the hypoxanthine/xanthine oxidase system (HXXO) or by the redox cycler 2,3-dimethoxy-1,4-naphtoquinone, caused a marked amplification of IL-1β-primed, steady state, MMP-9 mRNA level and an increase in gelatinolytic activity in the conditioned medium. Superoxide generators alone were ineffective. Cytokine-induced steady state mRNA levels of TIMP-1, an endogenous inhibitor of MMP-9, were affected similarly by HXXO. Transient transfection of rat mesangial cells with 0.6 kb of the 5′-flanking region of the rat MMP-9 gene proved a transcriptional regulation of MMP-9 expression by superoxide. HXXO augmented the IL-1β-triggered nuclear translocation of p65 and c-Jun and, in parallel, increased DNA binding activities of NF-κB and AP-1. Mutation of either response element completely prevented MMP-9 promoter activation by IL-1β. Moreover, specific inhibitors of the classical extracellular signal-regulated kinase (ERK) pathway and p38 mitogen-activated protein kinase (MAPK) cascade, partially reversed the HXXO-mediated effects on MMP-9 mRNA levels, thus demonstrating involvement of ERKs and p38 MAPKs in MMP-9 expression. Furthermore, IL-1β-triggered phosphorylation of all three MAPKs, including p38-MAPK, c-Jun N-terminal kinase, and ERK, was substantially enhanced by superoxide. Our data identify superoxide as a costimulatory factor amplifying cytokine-induced MMP-9 expression by interfering with the signaling cascades leading to the activation of AP-1 and NF-κB.

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“…On the basis of reports that sustained activation of c-Jun N-terminal kinase (JNK) contrib- utes to endothelial cell apoptosis (27,28), we reasoned that PR3 and/or HNE may be activating the JNK pathways as part of the mechanism to induce apoptosis. We compared the activation status of three stress-related pathways, including JNK, extracellular signal-regulated protein kinase (ERK), and p38 mitogen-activated protein kinase (p38 MAPK) ( Figure 5A), using phospho-specific Abs.…”

Section: Pr3 and Hne Affect Signal Transduction Pathwaysmentioning

confidence: 99%

Novel Effects of Neutrophil-Derived Proteinase 3 and Elastase on the Vascular Endothelium Involve In Vivo Cleavage of NF-κB and Proapoptotic Changes in JNK, ERK, and p38 MAPK Signaling Pathways

Preston

Zarella²,

Pendergraft³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. Leukocyte-derived proteases have long been considered simply degradative. However, emerging data raise possibilities of a complex and specific biologic role for these proteases in substrate processing and in signaling pathways within cells. This study reports that the release of neutrophilic and monocytic proteases, such as proteinase 3 (PR3) and human neutrophil elastase (HNE), can result in their entry into endothelial cells coincident with the activation of proapoptoticsignaling events through ERK, JNK, and p38 MAPK. Inhibition of JNK blocked PR3-induced apoptosis, and inhibition of p38 MAPK blocked PR3-and HNE-induced apoptosis, indicating that these pathways are required for activation of apoptosis. It is here shown that protease entry results in direct cleavage of p65 NF-B in the N-terminal region by PR3 and in the C-terminal region by HNE. This cleavage results in diminished transcriptional activity by NF-B as demonstrated by diminished levels of TNF-␣-induced IL-8 message in the presence of PR3 or HNE. Inhibition of caspases did not block the cleavage of p65 NF-B, and sequence analysis showed that the PR3 and HNE cleavage sites are unique with respect to reported caspase sites. The data demonstrate that PR3 and HNE have specific, fundamental roles in endothelial responses during inflammation. Upon entry, they can usurp the cell's control of its own fate by directly intervening into caspase cascades. This provides a unique mechanism of crosstalk between leukocytes and endothelial cells at sites of inflammation that impacts both cytokine networks and cell viability.

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Nitric oxide stimulates stress‐activated protein kinases in glomerular endothelial and mesangial cells

Cited by 56 publications

References 42 publications

Nitric oxide contributes to cytokine-induced apoptosis in pancreatic beta cells via potentiation of JNK activity and inhibition of Akt

Nitric oxide contributes to cytokine-induced apoptosis in pancreatic beta cells via potentiation of JNK activity and inhibition of Akt

Amplification of IL-1β-Induced Matrix Metalloproteinase-9 Expression by Superoxide in Rat Glomerular Mesangial Cells Is Mediated by Increased Activities of NF-κB and Activating Protein-1 and Involves Activation of the Mitogen-Activated Protein Kinase Pathways

Novel Effects of Neutrophil-Derived Proteinase 3 and Elastase on the Vascular Endothelium Involve In Vivo Cleavage of NF-κB and Proapoptotic Changes in JNK, ERK, and p38 MAPK Signaling Pathways

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