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

高血糖和肾小球高血压导致系膜细胞功能障碍的分子机制

• 批准号: 10671063
• 负责人: HANEDA Masakazu
• 金额: $ 2.43万
• 依托单位: SHIGA UNIVERSITY OF MEDICAL SCIENCE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671063/
• 关键词: Diabetic nephropathy; Mesangial cells; Stretch stress; extracellular signal-regulated kinase (ERK); extracellular matrix protein; TGF-β; cGMP; cAMP; cAMP; メサンギウム細胞; 細胞外基質; MAP kinase; ブドウ糖過剰

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.

高血糖和肾小球高血压被认为是导致糖尿病肾病发生的主要因素。尽管发现这两个因素都会导致系膜细胞功能障碍，但其确切机制尚未完全阐明。在本研究中，我们清楚地证明，肾小球高血压引起的机械牵张能够通过激活蛋白酪氨酸激酶来激活细胞外信号调节激酶（ERK）和c-Jun NH2末端激酶（JNK），从而增加AP-1的DNA结合活性，从而增强系膜细胞中TGF-β和纤连蛋白（FN）的表达。 MEK 抑制剂能够抑制拉伸诱导的 AP-1 DNA 结合活性的增加以及 TGF-β 和 FN 产生的增强。由于我们发现高血糖可以以蛋白激酶C（PKC）依赖性方式激活ERK，因此两种因素激活ERK的机制似乎不同。因此，我们发现高血糖和拉伸应激对 ERK 激活和 FN 产生具有累加效应。此外，我们发现可以增加细胞 cAMP 或 cGMP 的药物能够阻止拉伸诱导的 ERK 激活和 FN 产生的增强。这些结果表明，ERK 通过不同的机制在高血糖和肾小球高血压下的系膜细胞功能障碍的发展中发挥关键作用。

项目成果

Ishida T,Haneda M, et al.: "Stretch-induced overproduction of fibronectin in mesangial cells is mediated by the activation of mitogen-activated protein kinase"Diabetes. 48. 595-602 (1999)

Ishida T、Haneda M 等人：“拉伸诱导的系膜细胞中纤连蛋白的过量产生是由丝裂原激活蛋白激酶的激活介导的”糖尿病。

Ishida T,Haneda M,et al.: "Stretch-induced overproduction of fibronectin in mesangial cells is mediated by the activation of mitogen-activated protein kinase." Diabetes. Vol48 (in press). (1999)

Ishida T、Haneda M 等人：“拉伸诱导的系膜细胞中纤连蛋白的过量产生是由丝裂原激活蛋白激酶的激活介导的。”

Ishida T, Haneda M, Maeda S, Koya D, Kikkawa R.: "Stretch-induced overproduction of fibronectin in mesangial cells is mediated by the activation of mitogen-activated protein kinase."Diabetes. 48. 595-602 (1999)

Ishida T、Haneda M、Maeda S、Koya D、Kikkawa R.：“拉伸诱导的系膜细胞中纤连蛋白的过量产生是由丝裂原激活蛋白激酶的激活介导的。”糖尿病。