Abstract
Advanced glycation end-products (AGEs) are products generated by non-enzymatic glycation (Maillard reaction). In diabetic patients, chronic hyperglycemia accelerates the production and accumulation of AGEs. AGEs can cause tissue damage through change of proteins structure and function, and stimulation of oxidative stress and inflammatory responses by binding to specific receptors (ex: RAGE). AGEs has been implicated in aging and many diseases. Furthermore, N-acetyl-L-cysteine (NAC), the acetylated variant of the L-cysteine, is a free-radical scavenger, and a precursor of glutathione. NAC can be a nutritional supplement and clinical drug. In this study, we investigated the regulation of the PI3K/AKT signaling pathway by AGEs, high glucose and NAC in 3T3-L1 preadipocytes. We found that treatment with AGEs activated both Src and AKT, and induced the production of reactive oxygen species in 3T3-L1 cells. Further, the AGEs-induced phosphorylation of AKT was inhibited by Src inhibitor SKI, and the AGEs-induced phosphorylation of Src was inhibited by NADPH oxidase (NOX) inhibitor DPI. In glucose-cultured 3T3-L1 cells, basal Src and AKT were activated. In addition, the glucose-induced phosphorylation of AKT was inhibited by SKI and DPI, and the glucose-induced phosphorylation of Src was inhibited by DPI. These results indicated that both AGEs and high glucose activated Src through a NOX-dependent mechanism, and activated Src subsequently induced phosphorylation of AKT in 3T3-L1 cells. Moreover, treatment with NAC activated PI3K/AKT signaling pathway in 3T3-L1 cells, and was probably not mediate by NAC’s antioxidant function.