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

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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.