MOLECULAR MECHANISM OF MESANGIAL CELL DYSFUNCTION DUE TO HYPERGLYCEMIA AND GLOMERULAR HYPERTENSION

高血糖和肾小球高血压被认为是糖尿病肾病发生的主要因素。虽然这两个因素都被发现导致系膜细胞功能障碍，但其确切的机制尚未完全阐明。在本研究中，我们清楚地证明了肾小球高血压机械牵拉能够通过蛋白酪氨酸激酶的激活而激活细胞外信号调节激酶和c-jun氨基末端激酶，增加AP-1DNA结合活性，从而增强转化生长因子-β和纤维连接蛋白(FN)的表达。MEK抑制剂能抑制牵张诱导的AP-1DNA结合活性的增加以及转化生长因子-β和FN产生的增加。由于我们发现高血糖可以通过蛋白激酶C(PKC)依赖的方式激活ERK，所以两种因素激活ERK的机制似乎不同。因此，我们发现高血糖和拉伸应激对ERK的激活和FN的产生具有相加的作用。此外，我们还发现，能够增加细胞内cAMP或cGMP的药物能够阻止牵张诱导的ERK激活和FN产生的增加。这些结果表明，ERK在高血糖和肾小球高血压时肾小球系膜细胞功能障碍的发生发展中起着关键作用。

Hyperglycemia and glomerular hypertension are considered to be main factors responsible for the development of diabetic nephropathy. Although both factors were found to cause mesangial cell dysfunction, the precise mechanisms have not been fully elucidated yet. In the present study, we clearly demonstrated that mechanical stretch due to glomerular hypertension was able to activate extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) through the activation of protein tyrosine kinase, to increase DNA binding activity of AP-1, and thus to enhance the expression of TGF-β and fibronectin (FN) in mesangial cells. An inhibitor of MEK was able to inhibit stretch-induced increase in DNA binding activity of AP-1 and enhancement of TGF-β and FN production. Since we found that hyperglycemia could activate ERK in protein kinase C (PKC)-dependent manner, the mechanism of ERK activation by both factors seems to be different. Thus, we found the additive effect of hyperglycemia and stretch stress on ERK activation and FN production. Furthermore, we found that the agents which could increase cellular cAMP or cGMP were able to prevent stretch-induced activation of ERK and enhancement of FN production. These results indicate that ERK plays a key role in the development of mesangial cell dysfunction under both hyperglycemia and glomerular hypertension through different mechanisms.