| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1995: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1994: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Research Abstract |
We have previously shown that mesangial cell dysfunction in diabetes plays an important role in the development of diabetic nephropathy. However, the molecular mechanisms of mesangial cell disfunction in diabetes have not been clarified yet. Mitogen-activated protein kinase (MAPK) cascade has been shown to play a key role in the signal transduction system leading to various cellular functions. MAPK cascade is known to be activated when protein kinase C (PKC) is activated and we have shown that PKC is activated in mesangial cells cultured under high glucose conditions. Therefore, in this project, we have attempted to examine the charactors of MAPK cascade in mesangial cells and its abnormalities in diabetes. The following results were obtained ;
1. In mesangial cells, MAPK cascade was activated by various vasoconstrictive peptides and PKC activation. This activation was inhibited by agents which increace cellular cAMP or cGMP.
2. In mesangial cells cultured under high glucose conditions, MAPK cascade was activated in PKC-dependent manner. cPLA2, a enzyme downstream to MAPK,was also activated.
3. The activation of MAPK cascade was also observed in glomeruli isolated from diabetic rats and this activation was prevented by the treatment with insulin.
These results indicate that, in mesangial cells cultured under high glucose conditions and in diabetic glomeruli, and elevation of PKC activities may lead to the activation of MAPK cascade. The activation of MAPK cascade resulted in the activation of cPLA2, which might contribute ot the development of glomerular hyperfiltration through the production of prostanoids. Therefore, the activation of MAPK cascade found in this study might play a key role in the development of mesangial cell dysfunction in diabetes.
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