High glucose-induced O-GlcNAcylated carbohydrate response element-binding protein (ChREBP) mediates mesangial cell lipogenesis and fibrosis: the possible role in the development of diabetic nephropathy

• Published in: The Journal of biological chemistry Vol. 289; no. 19; pp. 13519 - 13530
• Main Authors: Park, Min-Jung, Kim, Dong-Il, Lim, Seul-Ki, Choi, Joo-Hee, Han, Ho-Jae, Yoon, Kyung-Chul, Park, Soo-Hyun
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 09.05.2014
• Subjects: Acetylglucosamine - analogs & derivatives; Acetylglucosamine - pharmacology; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; beta-N-Acetylhexosaminidases - biosynthesis; Cholesterol - biosynthesis; Cholesterol - genetics; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetic Nephropathies - chemically induced; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Fibrosis - chemically induced; Fibrosis - genetics; Fibrosis - metabolism; Fibrosis - pathology; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - genetics; Glucose - pharmacology; HEK293 Cells; Humans; Lipogenesis - drug effects; Mesangial Cells - metabolism; Mesangial Cells - pathology; Molecular Bases of Disease; Oximes - pharmacology; Phenylcarbamates - pharmacology; Rats; Sweetening Agents - pharmacology; Triglycerides - biosynthesis; Triglycerides - genetics; O-GlcNAcylation; Kidney Metabolism; Diabetes; Lipogenesis; Fibrosis
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.530139

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-α, 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.