ABNORMAL SIGNAL TRUNSDUCTION IN MESANGIAL CELLS IN DIABETES

我们以前已经表明，糖尿病肾小球系膜细胞功能障碍在糖尿病肾病的发展中起着重要作用。然而，糖尿病系膜细胞功能障碍的分子机制尚未阐明。丝裂原活化蛋白激酶（MAPK）级联反应在细胞信号转导系统中起着重要作用。已知当蛋白激酶C（PKC）被激活时，MAPK级联被激活，并且我们已经表明在高糖条件下培养的系膜细胞中PKC被激活。因此，本课题试图研究糖尿病患者系膜细胞MAPK级联反应的特点及其异常。获得了以下结果：1。在系膜细胞中，MAPK级联反应被多种缩血管肽和PKC激活所激活。这种激活被增加细胞cAMP或cGMP的试剂抑制。在高糖条件下培养的系膜细胞中，MAPK级联以PKC依赖的方式被激活。MAPK下游酶cPLA2也被激活.在离体糖尿病大鼠肾小球中也观察到MAPK级联反应的激活，而这种激活可被胰岛素抑制，提示高糖培养的肾小球系膜细胞和糖尿病大鼠肾小球中，PKC活性的升高可能导致MAPK级联反应的激活。MAPK级联反应的激活导致cPLA2的激活，cPLA2可能通过产生前列腺素参与肾小球高滤过的发生。因此，本研究中发现的MAPK级联激活可能在糖尿病系膜细胞功能障碍的发展中起关键作用。

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.