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Diabetes 51:3505-3509, 2002
© 2002 by the American Diabetes Association, Inc.
Inhibition of the JAK/STAT Signaling Pathway Prevents the High Glucose-Induced Increase in TGF-ß and Fibronectin Synthesis in Mesangial Cells
1 Vascular Biology Center, Medical College of Georgia, Augusta, Georgia
2 Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia
3 Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia
High glucose (HG) causes glomerular mesangial cell (GMC) growth, production of transforming growth factor (TGF)-ß, and increased synthesis of matrix proteins such as fibronectin, contributing to diabetic nephropathy. We recently found that exposure of cells to HG also activates the growth-promoting enzyme janus kinase 2 (JAK2) and its latent signal transducers and activators of transcription (STAT) transcription factors (STAT1, STAT3, and STAT5). Our purpose was to determine the effect that inhibition of JAK2 and these STAT transcription factors has on the HG-induced increase in TGF-ß and fibronectin synthesis in GMC. Exposure of GMC to 25 mmol/l glucose caused the activation of JAK2, STAT1, STAT3, and STAT5 plus an increase in TGF-ß and fibronectin synthesis, as compared with 5.5 mmol/l glucose. This HG-induced increase in synthesis of TGF-ß and fibronectin was prevented by concomitant incubation with AG-490, a specific JAK2 inhibitor. The HG-induced JAK2, STAT1, and STAT3 tyrosine phosphorylations in GMC were also abolished by AG-490. Preincubation of GMC cultured in 25 mmol/l glucose with a specific JAK2 or STAT1 antisense oligonucleotide also prevented both TGF-ß and fibronectin synthesis. These results provide direct evidence for linkages between JAK2, STAT1, and the glucose-induced overproduction of TGF-ß and fibronectin in GMC.
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