Role of MCP-1/CCR2 in renal fibrosis

MCP-1/CCR2 在肾纤维化中的作用

• 批准号: 14571019
• 负责人: WADA Takashi
• 金额: $ 2.24万
• 依托单位: KANAZAWA UNIVERSITY
• 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-14571019/
• 关键词: chemokine; chemokine recepor; kidney; MCP-1; CCR2; macrophage; fibrosis; TGF-β

Studies of chemokines and their cognate receptors have shed light on the detailed molecular mechanisms of leukocyte trafficking and activation in various inflammatory diseases including renal ones.Chemokine receptors expressed on renal resident cells might be involved in proliferation, proteinuria and fibrogenesis.Novel biological functions of chemokines would expand their universe beyond chemotaxis and activation of inflammatory cells in renal diseases. Importantly, MCP-1 and its cognate receptor CCR2 are now considered to contribute to progressive renal fibrosis, which is a hallmark of progressive renal diseases despite their etiologies, including diabetic nephropathy.The selective intervention of MCP-1-CCR2 via the administration of anti-MCP-1 neutralizing antibodies, CCR2 antagonists and the MCP-1 mutant ameliorated progressive renal fibrosis by resulting in decrease in the deposit of type I collagen and in reduced expression of TGF-p. This MCP-1-CCR2-dependent loop for progressive renal fibrosis was confirmed in CCR2 gene targeted mice.These findings suggest that the therapeutic strategy of blocking MCP-1-CCR2 may prove beneficial for progressive renal fibrosis.

趋化因子及其受体的研究揭示了包括肾脏在内的各种炎症性疾病中白细胞运输和活化的分子机制，表达于肾脏驻留细胞的趋化因子受体可能参与了细胞增殖、蛋白尿和纤维化的发生，其新的生物学功能将使趋化因子的研究领域从趋化和活化炎症细胞扩展到肾脏疾病。重要的是，MCP-1及其同源受体CCR 2现在被认为有助于进行性肾纤维化，其是进行性肾病的标志，尽管其病因包括糖尿病肾病。CCR 2拮抗剂和MCP-1突变体通过导致I型胶原存款减少和TGF-β表达减少来改善进行性肾纤维化。在CCR 2基因靶向小鼠中证实了进行性肾纤维化的依赖环，这些发现表明阻断MCP-1-CCR 2的治疗策略可能对进行性肾纤维化有益。

项目成果

Wada T, Razzaque MS, Matsushima K, et al.: "Cellular and molecular basis of fibrogenesis"Landes Bioscience(In press). (2004)

Wada T、Razzaque MS、Matsushima K 等：“纤维发生的细胞和分子基础”Landes Bioscience（正在出版）。

Kitagawa K, Wada T, Furuichi K, et al.: "Blockade of CCR2 ameliorates progressive fibrosis in kidney"Am J Pathol. In press. (2004)

Kitakawa K、Wada T、Furuichi K 等人：“阻断 CCR2 可改善肾脏进行性纤维化”Am J Pathol。

Wada T, Furuichi K, Sakai N, et al.: "Gene therapy via blockade of MCP-1 for renal fibrosis"J Am Soc Nephrol. (In press). (2004)

Wada T、Furuichi K、Sakai N 等人：“通过阻断 MCP-1 治疗肾纤维化的基因治疗”J Am Soc Nephrol。

Furuichi K, Wada T, Iwata Y, et al.: "Gene therapy expressing amino-terminal truncated monocyte chemoattractant protein-1 prevents renal ischemia-reperfusion injury"J Am Soc Nephrol. (In press). (2003)

Furuichi K、Wada T、Iwata Y 等人：“表达氨基末端截短的单核细胞趋化蛋白-1 的基因疗法可预防肾缺血再灌注损伤”J Am Soc Nephrol。

Furuichi K, Wada T, Iwata Y, et al.: "CCR2 signaling contributes to ischemia-reperfusion injury in kidney."J Am Soc Nephrol. 14(10). 2503-2515 (2003)

Furuichi K、Wada T、Iwata Y 等人：“CCR2 信号传导导致肾脏缺血再灌注损伤。”J Am Soc Nephrol。