Advanced glycosylation end products induce inducible nitric oxide synthase ( iNOS) expression via a p38 MAPK-dependent pathway.
BACKGROUND: Advanced glycosylation end products (AGEs) accumulation in tissue has been implicated in diabetic related complications, including diabetic nephropathy. Activation of peroxisome proliferator activated receptor-gamma ( PPAR-gamma) ameliorates diabetic nephropathy. METHODS: In the present study, we investigated the effects of AGEs on inducible nitric oxide synthase ( iNOS) expression and nitric oxide production, and the effects of rosiglitazone, an activator of PPAR-gamma, on AGE-induced iNOS expression and nitrite release in glomerular mesangial cells. RESULTS: AGEs caused a dose- and time-dependent increase of iNOS induction and nitrite accumulation in mesangial cells. A protein tyrosine kinase inhibitor (genistein), or a p38 mitogen- activated protein kinase ( MAPK) inhibitor (SB203580) suppressed AGE- induced iNOS expression and nitrite release from mesangial cells. Addition of bovine serum albumin (BSA)-AGEs to mesangial cells increased p38 MAPK activities. Activation of PPAR-gamma by rosiglitazone inhibited AGE- induced iNOS expression, nitrite release, and p38 MAPK activation in mesangial cells. AGE-stimulated nitrite release was attenuated by pretreatment with anti-tumor necrosis factor-alpha ( TNF-alpha) and anti-transforming growth factor-beta ( TGF-beta) antibodies. AGE-induced iNOS expression was inhibited by treatment with a nuclear factor-kappaB (NF-kappaB) inhibitor, pyrrolidone dithiocarbamate. Addition of BSA-AGEs to mesangial cells stimulated p65 NF-kappaB translocation from the cytosol to the nucleus. CONCLUSION: These data suggest that cytokine release, NF-kappaB and p38 MAPK-dependent pathways may play a role in AGE- induced iNOS expression and subsequent nitric oxide production in mesangial cells. Rosiglitazone may prevent AGE-induced iNOS expression by interfering with p38 MAPK activity.[1]References
- Advanced glycosylation end products induce inducible nitric oxide synthase (iNOS) expression via a p38 MAPK-dependent pathway. Chang, P.C., Chen, T.H., Chang, C.J., Hou, C.C., Chan, P., Lee, H.M. Kidney Int. (2004) [Pubmed]
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