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.


CONCLUSIONS
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.
Chang
Po-Chiao
PC
Graduate Institute of Biomedical Technology, Taipei Medical University, Taipei, Taiwan.
Chen
Tso-Hsiao
TH
Chang
Chun-Jen
CJ
Hou
Chun-Cheng
CC
Chan
Paul
P
Lee
Horng-Mo
HM
D000818:Animals; D002417:Cattle; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects / Q000201:enzymology; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D047495:PPAR gamma / Q000819:agonists; D051381:Rats; D000077154:Rosiglitazone; D012710:Serum Albumin, Bovine / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016207:Cytokines; D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; C081628:advanced glycation end products-bovine serum albumin; D000077154:Rosiglitazone; D012710:Serum Albumin, Bovine; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases