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Clinical and experimental data indicate that anti-neutrophil cytoplasmic autoantibodies (ANCAsAnti-neutrophil cytoplasmic autoantibodies (ANCA) are specific for proteins in the cytoplasm of neutrophils and monocytes. The major target antigens in patients with vasculitis and glomerulonephritis are myeloperoxidase (MPO) and proteinase 3 (PR3). ANCAs occur in greater than 80% of patients with active untreated Wegener's granulomatosis, microscopic polyangiitis, and pauci-immune crescentic glomerulonephritis.1 There is compelling clinical and experimental evidence that ANCA IgG causes ANCA-associated vasculitis and glomerulonephritis. The strongest clinical evidence for causation is the observation that a newborn child developed glomerulonephritis and pulmonary hemorrhage shortly after delivery from a mother with MPO-ANCA-associated microscopic polyangiitis, apparently caused by transplacental transfer of ANCA IgG.2,3 Two compelling animal models of ANCA vasculitis and glomerulonephritis have been described by two different research groups.4,5 Xiao and colleagues 4 induced glomerulonephritis and systemic vasculitis by intravenous injection of either anti-MPO IgG or anti-MPO splenocytes derived from MPO knockout mice immunized with murine MPO. Induction of glomerulonephritis by anti-MPO IgG in this model is enhanced by cytokines 6 and requires neutrophils. 7 Little and colleagues 5 immunized rats with human MPO, resulting in the production of antibodies that cross reacted with rat MPO and caused vasculitis and glomerulonephritis. The pathogenic effects of these anti-MPO antibodies were augmented by cytokines.Numerous in vitro studies indicate that ANCA IgG can activate neutrophils and cause them to release proinflammatory factors. The expression of ANCA antigens (MPO and PR3) at the surface of neutrophils where they are accessible to interact with ANCA IgG is enhanced by proinflammatory cytokines, such as tu-

ACE-related carboxypeptidase (ACE2) may counterbalance the angiotensin (ANG) II-promoting effects of ACE in tissues where both enzymes are found. Alterations in renal ACE and ACE2 expression have been described in experimental models of diabetes, but ACE2 activity was not assessed in previous studies. We developed a microplatebased fluorometric method for the concurrent determination of ACE and ACE2 activity in tissue samples. Enzymatic activity (relative fluorescence unit [RFU] ⅐ g protein ؊1 ⅐ h ؊1 ) was examined in ACE and ACE2 knockout mice and in two rodent models of diabetes, the db/db and streptozotocin ( and r ‫؍‬ ؊0.522, respectively). We conclude that in renal cortex from diabetic mice, ACE2 expression is increased at the posttranscriptional level. The availability of an assay for concurrent measurement of ACE and ACE2 activity should be helpful in the evaluation of kidney-specific alterations in the balance of these two carboxypeptidases, which are involved in the control of local ANG II formation and degradation. Diabetes 55

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Necrotizing and crescentic GN (NCGN) with a paucity of glomerular immunoglobulin deposits is associated with ANCA. The most common ANCA target antigens are myeloperoxidase (MPO) and proteinase 3. In a manner that requires activation of the alternative complement pathway, passive transfer of antibodies to mouse MPO (anti-MPO) induces a mouse model of ANCA NCGN that closely mimics human disease. Here, we confirm the importance of C5aR/CD88 in the mediation of anti-MPO-induced NCGN and report that C6 is not required. We further demonstrate that deficiency of C5a-like receptor (C5L2) has the reverse effect of C5aR/CD88 deficiency and results in more severe disease, indicating that C5aR/CD88 engagement enhances inflammation and C5L2 engagement suppresses inflammation. Oral administration of CCX168, a small molecule antagonist of human C5aR/CD88, ameliorated anti-MPO-induced NCGN in mice expressing human C5aR/CD88. These observations suggest that blockade of C5aR/CD88 might have therapeutic benefit in patients with ANCA-associated vasculitis and GN.