期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 19, 页码 13519-13530出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.530139
关键词
Diabetes; Fibrosis; Kidney Metabolism; Lipogenesis; O-GlcNAcylation
资金
- Korean Science and Engineering Foundation [2011-0016649]
- National Research Foundation of Korea [2011-0016649] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Background: Abnormal lipid synthesis and fibrosis can lead to diabetic nephropathy. Results: High glucose-induced O-GlcNAcylated ChREBP increases the expression of lipogenic and fibrotic proteins and induces lipid accumulation and fibrosis. Conclusion:O-GlcNAcylated ChREBP mediates lipogenesis and fibrosis in mesangial cells. Significance: This is the first report that O-glycosylated ChREBP plays a pathophysiological role in lipogenesis and fibrosis in mesangial cells. Carbohydrate response element-binding protein (ChREBP) is a transcription factor responsible for carbohydrate metabolism in the liver. However, the role of ChREBP in diabetic nephropathy has not been elucidated. Thus, we investigated the role of ChREBP in mesangial cells in diabetic nephropathy. Treatment with 25 mm glucose (high glucose; HG) increased cellular O-GlcNAc and O-GlcNAcylated ChREBP in mesangial cells compared with normal 5.5 mm glucose. O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino N-phenylcarbamate (PUGNAc), a drug that increases O-GlcNAc, augmented the expression of ChREBP targets, whereas DON, a drug that decreases O-GlcNAc and O-GlcNAcase overexpression, mitigated the increase with HG. O-GlcNAc augmented the protein stability, transcriptional activity, and nuclear translocation of ChREBP. HG treatment also stimulated lipid accumulation and the contents of triglyceride and cholesterol in mesangial cells. In addition, HG triggered expression of hypoxia-inducible factor 1-, vascular endothelial growth factor, and extracellular matrix components related to nephrosclerosis. The ChREBP mutant, W130A, did not exhibit HG-induced lipid accumulation and fibrotic proteins, suggesting that the Trp-130 residue in the MCR3 domain is important in the development of glomerulosclerosis. O-GlcNAcylated ChREBP was elevated in mesangium cells of streptozotocin-induced diabetic rats. In conclusion, HG increased the O-GlcNAcylated ChREBP level, which resulted in lipid accumulation and up-regulation of fibrotic proteins in mesangial cells. These effects may lead mesangial cells to an ultimately pathological state.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据