Korean Diabetes Journal 1999;23(5):635-646.
Published online January 1, 2001.
Effect of Protein Kinase C Inhibitors on Expression of TGF-betamRNA in Cultured Mesangial Cells Under High Glucose Concentration.
Yoon Sang Choi, Dong Seop Choi
Abstract
BACKGROUND
Diabetic nephropathy is characterized by hypertrophy of both glomerular and tubular elements, thickening of the glomerular and tubular basement membranes, progressive accumulation of extracellular matrix components in mesangium, and tubulointerstitial fibrosis. Hyperglycemia increases the level of diacylglycerol (DAG) and activates protein kinase C (PKC) in mesangial cells and other vascular tissues. PKC activation regulates a number of vascular functions such as vascular permeability, contractility, cellular proliferation, basement membrane synthesis, signal transduction mechanisms for hormones and growth factors, In addition, glomerular mesangial cells play an important role in the development of diabetic nephropathy. Mesangial cells have many functions such as contractile properties, phagocytosis of macromolecules, synthesis of matrix proteins, and production of and response to growth factors (e.g., PDGF, TGF beta). Also, these growth factors play important roles for mesangial cell proliferation and in pathophysiology of diabetic nephropathy. Specifically, TGF beta is a key mediator in development of diabetic nephropathy. This study was performed to evaluate the relationship between PKC activation and TGF f3 production in mesangial cells under high glucose condition. METHODS: The expression of the TGF beta mRNA was evaluated in cultured human mesangial cells by semiquantitive RT-PCR, under varying degree of glucose concentrations (5 mM, 10 mM, 30 mM) with and without treatment of PKC inhibitors (calphostin C, Vitamin-E). RESULT: In control group (no treatment), ratio of TGF beta/beta-aetin mRNA in 5mM, 10mM, 30mM glucose were 1.694+/-0.223, 3.383+/-2.089, 5,474+/-1.74S, respectively. In calphostin C treated group, ratio of TGF beta/beta-actin mRNA in 5mM, 10mM, 30mM glucose were 1.457+/-0,322, 1.379+/-0.138, 1.205+/-0.050, respectively. In vitamin E treated group, ratio of TGF beta/beta-actin mRNA in 5mM, 10rnM, 30mM glucose were 1.198+/-0.081, 1.995+/-1.625, O.S04+/-0.570, respectively. In 10mM glucose concentration, ratios of TGF beta/beta-actin mRNA were reduced in calphostin C and vitamin E treated groups, compared with those in control group. But, there were no statistical significancies (p=0.191, 0.208). In high glucose concentration (30mM), ratios of TGF /3/f3-actin mRNA were significantly reduced in calphostin C and vitamin E treated groups compared with those in control group (p<0.05), respectively. CONCLUSIONS: These results indicate that high glucose concentration induce TGF beta expression in eultured mesangial cells through PKC activation. This suggests that selective PKC beta isoform inhibitors may be useful for treatment and prevention of diabetie nephropathy.
Key Words: Mesangial cell, PKC (protein kinase C), TGF beta, Vitamin E, Calphostin C


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