Investigation of the pathophysiological significance of big mitogen-acivated protein kinase 1 in diabetic nephropathy for the development of molecular-targeted drugs

大丝裂原激活蛋白激酶1在糖尿病肾病中的病理生理学意义研究对分子靶向药物开发的意义

• 批准号: 14570078
• 负责人: YOSHIZUMI Masanori
• 金额: $ 1.98万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570078/
• 关键词: MAP kinase; Big MAP kinase 1; diabetic nephropathy; mesangial cell; OLETF rat; Dahl rat; angiotensin II; antioxidant; Dahlラット; big MAP kinase 1; oxidative stress; osmotic stress; diabetic nephrophthy; c-Src tyrosine kinase; protein kinase C

In the current research project, we investigated the pathophysiological significance of big mitogen-acivated protein kinase 1 in diabetic nephropathy for the development of molecular-targeted drugs.1)In cultured rat mesangial cells; big mitogen-activated protein kinase 1 (BMK1) was activated by high glucose stimulation in a time and concentration-dependent manner. Protein kinase C and c-Src were suggested to be involved in BMK1 activation. From the results of transfection with dominant-negative MEKS to the cells, BMK1 was suggested to be involved in mesangial cell proliferation, which is one of the causes of diabetic nephropathy.2)In type 2 diabetic rat model OLETF, BMKI was activated in the glomeruli at 52 weeks of age with apparent proteinuria. In addition, BMK1 was also activated in the kidney of rat models of salt-sensitive hypertension (Dahl rats) and aldosterone-infused rats. From these results, it was suggested that BMKI activation is involved not only in diabetic nephropathy but also in hypertensive kidney injury.3)In disease model rats, treatment with antioxidants or angiotensin II receptor antagonist ameliorated renal injury with concomitant decrease in BMK1 activity. Therefore, it was suggested that BMK1 is involved in the progression of several renal diseases, such as diabetic nephropathy and other etiologies.4) In circulation, laminar fluid shear stress is atheroprotective whereas turbulent fluid shear stress is prone to atherosclerotic. In human umbilical vein endothelial cells (HUVEC), laminar fluid shear stress inhibited tumor necrosis factor alpha-induced c-Jun N-terminal kinase (JNK) activation. As a molecular mechanism of this inhibition, BMK1 activation was suggested to be a negative regulator of JNK activation.

在目前的研究项目中，我们研究了大丝裂原活化蛋白激酶1在糖尿病肾病中的病理生理意义，以开发分子靶向药物。1)培养大鼠系膜细胞；大丝裂原活化蛋白激酶1 （BMK1）在高糖刺激下呈时间和浓度依赖性激活。蛋白激酶C和C - src被认为参与了BMK1的激活。从MEKS显性阴性转染细胞的结果来看，BMK1参与了肾小球系膜细胞的增殖，这是糖尿病肾病的原因之一。2) 2型糖尿病OLETF模型大鼠在52周龄出现明显蛋白尿时，肾小球BMKI被激活。此外，BMK1在盐敏感性高血压大鼠模型（Dahl大鼠）和醛固酮注射大鼠的肾脏中也被激活。这些结果提示BMKI的激活不仅与糖尿病肾病有关，还与高血压肾损伤有关。3)在疾病模型大鼠中，抗氧化剂或血管紧张素II受体拮抗剂治疗可改善肾损伤，同时降低BMK1活性。因此，BMK1参与了多种肾脏疾病的进展，如糖尿病肾病和其他病因。4)在循环过程中，层流剪切应力对动脉粥样硬化具有保护作用，而湍流剪切应力易导致动脉粥样硬化。在人脐静脉内皮细胞（HUVEC）中，层流剪切应力抑制肿瘤坏死因子α诱导的c-Jun n -末端激酶（JNK）的激活。作为这种抑制的分子机制，BMK1激活被认为是JNK激活的负调节因子。

项目成果

Nishiyama A, et al.: "Effects of AT1 receptor blockade on renal injury and mitogen-activated protein activity in Dah1 salt-sensitive rats"Kidney Inter.. 65. 972-981 (2004)

Nishiyama A 等人：“AT1 受体阻断对 Dah1 盐敏感大鼠肾损伤和丝裂原激活蛋白活性的影响”Kidney Inter.. 65. 972-981 (2004)

Kyaw M, et al.: "Src and Cas are essentially but differentially involved in angiotensin II-stimulated migration of vascular smooth muscle cells via ERK1/2 and JNK activation"Mol.Pharmacol.. 65. 832-841 (2004)

Kyaw M 等人：“Src 和 Cas 本质上但有区别地参与血管紧张素 II 通过 ERK1/2 和 JNK 激活刺激的血管平滑肌细胞迁移”Mol.Pharmacol.. 65. 832-841 (2004)

Nishiyama A, Yoshizumi M, T Rahman M, Kobori H, Seth DM, Miyatake A, Zhang GX, Yao L, Hitomi H, Shokoji T, Kiyomoto H, Kimura S, Tamaki I, Kohno M, Abe Y.: "Effects of AT_1 receptor blockade on renal injury and mitogen-activated protein activity in Dahl s

Nishiyama A、Yoshizumi M、T Rahman M、Kobori H、Seth DM、Miyatake A、Zhang GX、Yao L、Hitomi H、Shokoji T、Kiyomoto H、Kimura S、Tamaki I、Kohno M、Abe Y.：“效果

Yoshizumi M, Abe Ji, Tsuchiya K, Berk BC, Tamaki T.: "Atheroprotective effect of laminar fluid shear stress in endothelial cells : possible role of mitogen-activated protein kinases"J.Pharmacol.Sci.. 91,(3). 172-176 (2003)

Yoshizumi M、Abe Ji、Tsuchiya K、Berk BC、Tamaki T.：“内皮细胞层流流体剪切应力的动脉粥样硬化保护作用：丝裂原激活蛋白激酶的可能作用”J.Pharmacol.Sci.. 91，（3）。

Yoshizumi M, et al.: "Atheroprotecitve effect of laminar fluid shear stress in endothelial cells : possible role of mitogen-activated protein kinases"J.Pharmacol.Sci.. 91. 172-176 (2002)

Yoshizumi M 等：“内皮细胞中层流流体剪切应力的动脉粥样硬化效应：丝裂原激活蛋白激酶的可能作用”J.Pharmacol.Sci.. 91. 172-176 (2002)