Advanced glycosylation end products induce inducible nitric oxide synthase (iNOS) expression via a p38 MAPK-dependent pathway

Po Chiao Chang, Tso Hsiao Chen, Chun-Jen Chang, Chun-Cheng Hou, Paul Chan, Horng Mo Lee

Research output: Contribution to journalArticlepeer-review

90 Citations (Scopus)


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-γ (PPAR-γ) 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-γ, 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-γ 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-α (TNF-α) and anti-transforming growth factor-β (TGF-β) antibodies. AGE-induced iNOS expression was inhibited by treatment with a nuclear factor-κB (NF-κB) inhibitor, pyrrolidone dithiocarbamate. Addition of BSA-AGEs to mesangial cells stimulated p65 NF-κB translocation from the cytosol to the nucleus. Conclusion. These data suggest that cytokine release, NF-κB 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.

Original languageEnglish
Pages (from-to)1664-1675
Number of pages12
JournalKidney International
Issue number5
Publication statusPublished - May 2004


  • AGEs
  • Mesangial cells
  • iNOS
  • p38 MAPK

ASJC Scopus subject areas

  • Nephrology


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