The Role of Anaphylatoxins, C3a, C5a, in Renal Injury.

过敏毒素、C3a、C5a 在肾损伤中的作用。

• 批准号: 11671033
• 负责人: MATSUO Seiichi
• 金额: $ 2.3万
• 依托单位: NAGOYA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671033/
• 关键词: renal injury; anaphylatoxins; anaphylatoxin receptors; C5a; C3a; thrombosis; carboxypeptidase; thrombomodulin; ラット実験腎炎; メサンギウム細胞; C5aレセプター拮抗ペプチド; 補体; 好中球

The following new findings were obtained by this research project.(A) The anaphylatoxin C5a plays an important role in glomerular thrombosis, which is one of the characteristic features of complement mediated severe glomerular injury.(B) A peptide, which specifically blocks C5a-receptor, effectively inhibits glomerular thrombosis in a rat model of experimental glomerulonephritis.(C) Recombinant human soluble thrombomodulin (RHS-TM) completely inhibits the glomerular thrombosis in this model, and this effect is partly mediated through the activation of proCPR (or TAFI) by TM-thrombin complex. Potato carboxypeptidase inhibitor (PCI), a specific inhbitor of CPR, ameliorated the antiinflammatory action of RHS-TM.Activated proCPR forms CPR and inactivates anaphylatoxins by removing the terminal arginine residues.(D) Anaphylatoxin receptors are expressed in the kidney and they are upregulated in human glomerulonephritis such as lupus nephritis.These results suggest that anaphylatoxins are the important byproducts during complement activation cascade which play important roles in the development of glomerular injury. Recently our group has cloned rat CPR.Since rat is the important animal which provides us a variety of renal injury models, we will be able to test the hypothesis by using recombinant CPR or CPR gene transfer that the control of anaphylatoxins will lessen the complement-mediated renal injury in vivo.

本研究项目获得以下新发现：(A) 过敏毒素C5a在肾小球血栓形成中发挥重要作用，肾小球血栓形成是补体介导的严重肾小球损伤的特征之一。(B) 一种特异性阻断C5a受体的肽，可有效抑制实验性肾小球肾炎大鼠模型中的肾小球血栓形成。(C) 重组人 在该模型中，可溶性血栓调节蛋白（RHS-TM）完全抑制肾小球血栓形成，这种作用部分是通过TM-凝血酶复合物激活proCPR（或TAFI）介导的。马铃薯羧肽酶抑制剂 (PCI) 是 CPR 的特异性抑制剂，可改善 RHS-TM 的抗炎作用。激活的 proCPR 形成 CPR，并通过去除末端精氨酸残基来灭活过敏毒素。(D) 过敏毒素受体在肾脏中表达，在狼疮等人类肾小球肾炎中表达上调 这些结果表明过敏毒素是补体激活级联过程中的重要副产物，在肾小球损伤的发生中发挥重要作用。最近我们课题组克隆了大鼠CPR。由于大鼠是为我们提供多种肾损伤模型的重要动物，我们将能够通过重组CPR或CPR基因转移来验证控制过敏毒素会减轻体内补体介导的肾损伤的假设。

项目成果

Mizuno M,Nishikawa K,Okada N,Matso S,Ito K,Okada H: "Inhibition of a membrane complement regulatory protein by a monocional antibody induces acute lethal shock in rats promed with lipoplysaccharide."Journal of Immunology. 162. 5477-5482 (1999)

Mizuno M、Nishikawa K、Okada N、Matso S、Ito K、Okada H：“单克隆抗体抑制膜补体调节蛋白会在脂多糖刺激的大鼠中诱导急性致死性休克。”免疫学杂志。

Watanabe M,Morita Y,Mizuno M,Nishikawa K,Matsuo S,et al.: "CD59 protects kidneys from complement mediated innjury in collaboration with Crry in rats."Kidney International. 58. 1569-1579 (2000)

Watanabe M、Morita Y、Mizuno M、Nishikawa K、Matsuo S 等人：“CD59 与 Crry 合作，在大鼠中保护肾脏免受补体介导的损伤。”肾脏国际。

Watanabe M, Morita Y, Mizuno M, Nishikawa K, Yuzawa Y, Hotta N, Morgan BP, Okada N, Okada N, Matsuo S: "CD59 protects kidneys from complement mediated innjury in collaboration with Crry in rats."Kidney International. 58. 1569-1579 (2000)

Watanabe M、Morita Y、Mizuno M、Nishikawa K、Yuzawa Y、Hotta N、Morgan BP、Okada N、Okada N、Matsuo S：“CD59 与 Crry 合作，在大鼠中保护肾脏免受补体介导的损伤。”肾脏国际。

Wakai K,Kawamura T,Matsuo S,Hotta N,Ohno Y: "Risk factor for IgA nephropathy : a case-control study in Japan."American Journal of Kidney Diseases. 33. 738-745 (1999)

Wakai K、Kawamura T、Matsuo S、Hotta N、Ohno Y：“IgA 肾病的危险因素：日本的病例对照研究。”美国肾脏病杂志。

Kato T,Akatsu H,Sato T,Matsuo S,et al.: "Molecular cloning and partial characterization of rat procarboxypeptidase R and carboxypeptidase N."Microbiology and Immunology. 44. 719-728 (2000)

Kato T、Akatsu H、Sato T、Matsuo S 等人：“大鼠羧肽酶原 R 和羧肽酶 N 的分子克隆和部分表征。”微生物学和免疫学。