Diabetes & Metabolism Journal

Original Articles

Effects of Troglitazone on the Expression of VEGF and TGF-beta in Cultured Rat Mesangial Cells.: Dong Lim Kim, Nan Hee Kim, Dong Seop Choi; Korean Diabetes J. 2007;31(3):220-229. Published online May 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.3.220

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Abstract PDF: BACKGROUND
Clinical study reported that troglitazone ameliorated microalbuminuria in diabetic nephropathy. However, the mechanism of action is not fully understood. Vascular endothelial growth factor (VEGF) is known as vascular permeability factor and it is considered the most likely cause of glomerular hyperfiltration and proteinuria in diabetic nephropathy. Transforming growth factor-beta (TGF-beta) is a potent inducer of extracellular matrix production and fibrosis in renal cells and one of the important cytokine in the pathogenesis of diabetic nephropathy. To determine whether troglitazone affects VEGF and TGF-beta production in diabetic nephropathy, we examined the effects of troglitazone on the VEGF and TGF-beta expression in cultured rat mesangial cells exposed to high glucose concentration. METHODS: Rat mesangial cells were cultured in media with D-glucose 5.5 mM (NG) or D-glucose 30 mM (HG), or D-glucose 30 mM/troglitazone 20 micrometer(HTz) and for 6, 24, or 72 hours, respectively. VEGF and TGF-beta expression were assessed by semiquantitative RT-PCR and western blot analysis. RESULTS: Troglitazone decreased the VEGF164 and VEGF120 mRNA expressions in cultured rat mesangial cells exposed to high glucose concentration with incubation for 24 and 72 hours, respectively. VEGF protein was also decreased in experimental group treated with troglitazone (HTz) than in those with HG for 24 and 72 hours. However troglitazone had no effect on the expression of TGF-beta mRNA in mesangial cells. CONCLUSION: This study suggested that troglitazone may modulate the development and progression of diabetic nephropathy by reducing the expression of VEGF in mesangial cells

Effect of Protein Kinase C Inhibitor on Glucose Transporter-1 (GLUT1) Expression in Cultured Rat Mesangial Cells.: Ie Byung Park, Dae Ryong Cha, Dong Rim Kim, Sin Gon Kim, Dong Hyun Shin, Kyung Mook Choi, Nan Hee Kim, Sei Hyun Baik, Dong Seop Choi; Korean Diabetes J. 2001;25(3):218-229. Published online June 1, 2001

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Abstract PDF: BACKGROUND
Recent studies have suggested that increased glucose uptake via GLUT1 may be a major determinant of glucose utilization and extracellular matrix formation in mesangial cells. This study was to evaluate the effect of protein kinase C inhibitor on glucose transporter-1 (GLUT1) expression in cultured rat mesangial cells. METHODS: The GLUT1 expression was evaluated in mesangial cells exposed to various glucose concentrations of media (5.5 mM, 15 mM or 30 mM) and incubation times (6 hr, 24 hr or 72 hr) by semiquantitative RT-PCR and western blot analysis. The effect of protein kinase C (PKC) inhibitor, calphostin C and phorbol 12-myristate 13-acetate (PMA) on GLUT1 expression was also evaluated under the same conditions. RESULTS: The GLUT1 mRNA expressions were significantly increased in MG (15 mM) and HG (30 mM) than those in NG (5.5 mM) with incubation of 6 hr, 24 hr and 72 hr, respectively. In HG media, the GLUT1 mRNA expression with incubation of 24 hr and 72 hr were significantly increased than that with incubation of 6 hr, respectively. In HG media, the GLUT1 mRNA expressions were significantly reduced in calphostin C and PMA treated groups compared with those in untreated groups. In western blot analysis of HG media, GLUT1 proteins were identified in PMA- or calphostin C-untreated group and PMA 6 hr treated group, but not identified in PMA 24 hr treated group and in calphostin C-treated groups with incubation of 6 hr and 24 hr. CONCLUSION: PKC inhibitors decrease glucose-induced GLUT1 expression under high glucose concentration in mesangial cells. These results suggest that PKC pathway may regulate GLUT1 expression under high glucose concentration in cultured rat mesangial cells.

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; Korean Diabetes J. 1999;23(5):635-646. Published online January 1, 2001

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Abstract PDF: 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.

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