Rhein reverses the diabetic phenotype of mesangial cells over‐expressing the glucose transporter (GLUT1) by inhibiting the hexosamine pathway

• Published in: British journal of pharmacology Vol. 153; no. 7; pp. 1456 - 1464
• Main Authors: Zheng, J‐M, Zhu, J‐M, Li, L‐S, Liu, Z‐H
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-04-2008; Nature Publishing; Nature Publishing Group
• Subjects: Animals; anthraquinone compound; Anthraquinones - pharmacology; Biological and medical sciences; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21 - drug effects; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Diabetes. Impaired glucose tolerance; diabetic nephrology; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - physiopathology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Inhibitors - pharmacology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Gene Expression Regulation - drug effects; Glucose Transporter Type 1 - drug effects; Glucose Transporter Type 1 - metabolism; GLUT1; hexosamine pathway; Hexosamines - metabolism; Hypertrophy - metabolism; Male; Medical sciences; mesangial cells; Mesangial Cells - drug effects; Mesangial Cells - metabolism; Pharmacology. Drug treatments; Phenotype; Rats; Rats, Sprague-Dawley; Research Papers; rhein; Transforming Growth Factor beta1 - drug effects; Transforming Growth Factor beta1 - metabolism; Endocrinopathy; GLUT1; Anthraquinone derivatives; rhein; Mesangial cell; Diabetes mellitus; Gene overexpression; Laxative; Glucose; mesangial cells; Kidney; Renal glomerulus; anthraquinone compound; Phenotype; diabetic nephrology; Anthraquinone; Urinary system; hexosamine pathway; GLUT-1 glucose transporter; Hexosamine; Antirheumatic agent; Carrier protein
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/bjp.2008.26

Background and purpose: Rhein, an anthraquinone compound isolated from rhubarb, has been proved effective in treatment of experimental diabetic nephropathy (DN). To explore the mechanism of its therapeutic effect on DN, rhein was tested for its effect on the hexosamine pathway.
Experimental approach: The influence of rhein on cellular hypertrophy, fibronectin synthesis, glucose uptake, glutamine: fructose 6‐phosphate aminotransferase (GFAT) activity, UDP‐N‐acetylglucosamine (UDP‐GlcNAc) level and TGF‐β1 and p21 expression was evaluated in MCGT1 cells, a GLUT1 transgenic rat mesangial cell line. GFAT activity in normal rat mesangial cells in high glucose concentrations and in vitro was also measured.
Key results: Significantly increased fibronectin synthesis, cellular hypertrophy, much higher GFAT activity and UDP‐GlcNAc level and increased TGF‐β1 and p21 expression were found in MCGT1 cells cultured in normal glucose concentration. Rhein treatment decreased all these features of MCGT1 cells but did not exert a direct effect on GFAT enzymatic activity.
Conclusions and implications: There was over‐activity of the hexosamine pathway in MCGT1 cells, which may explain the higher expression of TGF‐β1 and p21, the cellular hypertrophy and the increased expression of extracellular matrix (ECM) components in the cells. By inhibiting the increased activity the hexosamine pathway, rhein decreased TGF‐β1 and p21 expression and thus contributed to the decreased cellular hypertrophy and ECM synthesis. Inhibition of the hexosamine pathway may be one of the mechanism through which rhein exerts its therapeutic role in diabetic nephropathy.
British Journal of Pharmacology (2008) 153, 1456–1464; doi:10.1038/bjp.2008.26; published online 11 February 2008