期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 146, 期 2, 页码 268-279出版社
WILEY
DOI: 10.1038/sj.bjp.0706309
关键词
diabetes; inflammation; oxidative stress; Amadori adducts; nitric oxide; nuclear factor-kappa B; mesothelial cells
1 Diabetes mellitus leads to a high incidence of several so-called complications, sharing similar pathophysiological features in several territories. Previous reports points at early nonenzymatic glycosylation products ( Amadori adducts) as mediators of diabetic vascular complications. In the present study, we analysed a possible role for Amadori adducts as stimulators of proinflammatory pathways in human peritoneal mesothelial cells (HPMCs). 2 Cultured HPMCs isolated from 13 different patients ( mean age 38.7716 years) were exposed to different Amadori adducts, that is, highly glycated haemoglobin ( 10 nM) and glycated bovine serum albumin ( 0.25 mg ml(-1)), as well as to their respective low glycosylation controls. Amadori adducts, but not their respective controls, elicited a marked increase of NF-kappa B activation, as determined by electromobility shift assays and transient transfection experiments. 3 Additionally, Amadori adducts significantly increased the production of NF-kappa B-related proinflammatory molecules, including cytokines, such as TNF-alpha, IL-1 beta or IL-6, and enzymes, such as cyclooxygenase- 2 and inducible nitric oxide ( NO) synthase, this latter leading to the release of NO by HPMCs. 4 The effects of Amadori adducts were mediated by different reactive oxygen and nitrosative species ( e. g. superoxide anions, hydroxyl radicals, and peroxynitrite), as they were blunted by coincubation with the appropriate scavengers. Furthermore, NO generated upon exposure to Amadori adducts further stimulated NF-kappa B activation, either directly or after combination with superoxide anions to form peroxynitrite. 5 We conclude that Amadori adducts can favour peritoneal inflammation by exacerbating changes in NO synthesis pathway and triggering NF-kappa B-related proinflammatory signals in human mesothelial cells.
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