Investigation of Integrin-mediated MAP kinase Signaling in Glomerulonephritis

肾小球肾炎中整合素介导的 MAP 激酶信号传导的研究

• 批准号: 12670756
• 负责人: KAGAMI Shoji
• 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: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670756/
• 关键词: Integrin; ECM remodeling; ERK signaling; Glomerular sclerosis

In order to control the function and behaviors of glomerular mesangial cell(MC) in progressive glomerulonephritis(GN), we investigated the integrin-mediated cell signaling pathway involved in MC adhesion on extracellular matrix (ECM). Cell proliferation, migration and collagen contraction assays revealed that α1β1 integrin -mediated ERK/AP-1 signaling is important pathway for pathological ECM remodeling seen in progressive GN. Either function-blocking antibody, ERK inhibitor (PD98059) or dominant negative c-jun vector (TAM67) inhibited α1β1 integrin -mediated ERK/AP-1 signaling in MC-induced pathological ECM remodeling. Administration of function-blocking anti- α1 integrin antibody into rats with anti-Thy-1 GN showed histological improvement with respect to MC proliferation and abnormal ECM remodeling compared with control anti-Thy-1 GN rats received control antibody. These results indicate that MC- α1β1 integrin- mediated ERK/AP-1 signaling play a critical role in pathological ECM remodeling in progressive GN.

为了研究肾小球系膜细胞（MC）在进行性肾小球肾炎（GN）中的功能和行为，我们研究了整合素介导的MC与细胞外基质（ECM）粘附的细胞信号通路。细胞增殖、迁移和胶原收缩试验表明，α1β1整合素介导的ERK/AP-1信号传导是进行性GN中观察到的病理性ECM重塑的重要途径。功能阻断抗体、ERK抑制剂（PD 98059）或显性失活c-jun载体（TAM 67）抑制MC诱导的病理性ECM重塑中α1β1整合素介导的ERK/AP-1信号传导。与接受对照抗体的对照抗Thy-1 GN大鼠相比，将功能阻断抗α1整合素抗体给予抗Thy-1 GN大鼠显示出MC增殖和异常ECM重塑方面的组织学改善。这些结果表明MC- α1β1整合素介导的ERK/AP-1信号在进行性GN的病理性ECM重塑中起关键作用。

项目成果

Kagami S et al: "Requirement for tyrosine kinase-ERK1/2 signaling in α1β1l integrin-mediated collagen matrix remodeling by rat mesangial cells"Exp Cell Res. 268. 274-283 (2001)

Kagami S 等人：“大鼠系膜细胞α1β1l 整合素介导的胶原基质重塑中酪氨酸激酶-ERK1/2 信号传导的要求”Exp Cell Res. 268. 274-283 (2001)

Shoji Kagami: "Requirement for tyrosine kinase-ERK1/2 signaling in α1β1 integrinmediated collagen matrix remodeling by rat mesangial cells"Exp Cell Res. 268. 274-283 (2001)

Shoji Kagami：“大鼠系膜细胞α1β1整合素介导的胶原基质重塑中酪氨酸激酶-ERK1/2信号传导的要求”Exp Cell Res. 268. 274-283 (2001)

Shoji Kagami: "Requirement for tyrosine kinase-ERK1/2 signaling in α1β1 integrin-mediated collagen matrix remodeling by rat mesangial cells"Exp Cell Res. 268. 274-283 (2001)

Shoji Kagami：“大鼠系膜细胞α1β1整合素介导的胶原基质重塑中酪氨酸激酶-ERK1/2信号传导的要求”Exp Cell Res. 268. 274-283 (2001)

Maki Urushihara: "Glomerular distribution and gekationolytic activity of metalloproteinases in human glomerulonephritis"Nephrol Dial Transplant. (in press). (2002)

Maki Urushihara：“人肾小球肾炎中金属蛋白酶的肾小球分布和解离活性”肾拨号移植。

Maki Urushihara: "Glomerular distribution and gelatinolytic activity of metalloproteinases in human glomerulonephritis"Nephrol Dial Transplant. (in press). (2002)

Maki Urushihara：“人肾小球肾炎中金属蛋白酶的肾小球分布和明胶溶解活性”肾拨号移植。