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

该研究项目获得了以下新发现。(A)过敏毒素C5 a在肾小球血栓形成中起重要作用，而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C5 a受体的肽，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)重组人可溶性血栓调节蛋白（RHS-TM）可完全抑制该模型中的肾小球血栓形成，其作用部分通过TM-凝血酶复合物激活proCPR（或TAFI）介导。马铃薯羧肽酶抑制剂（Potato carboxypeptidase inhibitor，PCI）可改善RHS-TM的抗过敏作用，激活后的proCPR可形成CPR，并通过去除末端精氨酸残基而使过敏毒素失活。(D)过敏毒素受体在肾脏表达，在狼疮性肾炎等肾小球疾病中表达上调，提示过敏毒素是补体激活级联反应的重要副产物，在肾小球损伤的发生发展中起重要作用。本课题组最近克隆了大鼠CPR，由于大鼠是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基因转移来验证体内过敏毒素的控制将减轻补体介导的肾损伤的假说。

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.