Induction of albuminuria in mice: synergistic effect of two monoclonal antibodies directed to different domains of aminopeptidase A.
Induction of albuminuria in mice: synergistic effect of two monoclonal antibodies directed to different domains of aminopeptidase A.
复制标题
诱导小鼠白蛋白尿：针对氨肽酶 A 不同结构域的两种单克隆抗体的协同作用。
作者：
S. Mentzel;J. V. van Son;H. Dijkman;J. Wetzels;K. Assmann
背景
氨基肽酶A是一种存在于足细胞上的酶，参与血管紧张素II的降解。在以前的小鼠研究中，我们使用了针对氨基肽酶A的单抗。我们观察到只有抑制氨基肽酶A酶活性的单抗才会引起蛋白尿。
方法
在这项研究中，研究了两种抗氨肽酶A单抗(单抗)联合注射的效果，这两种单抗分别针对与氨肽酶活性有关的两个不同结构域(ASD-3或ASD-37)和与酶活性部位无关的抗氨肽酶A单抗(ASD-41)。
结果
注射组合ASD-3/37(总4毫克，1：1)和ASD-37/41(总4毫克，1：1)，剂量在注射后第1天不会引起蛋白尿(4 Mg)，导致大量蛋白尿。ASD-3/41联合用药无效。这种蛋白尿不依赖于全身炎症免疫介质，也不可能仅仅与氨基肽酶A酶活性受阻有关。然而，蛋白尿的诱导与注射的单抗和氨基肽酶A在足细胞上的聚集有关。注射组合ASD-3/37或ASD-37/41不会导致全身血压升高。依那普利和氯沙坦的联合治疗降低了血压(未治疗的小鼠为53+/-10毫米汞柱，未治疗的小鼠为90+/-3毫米汞柱)，并将急性蛋白尿减少了55%(未治疗的小鼠为11,145+/-864微克白蛋白/18小时)。然而，使用三联疗法也观察到了类似的效果。因此，依那普利/氯沙坦联合治疗后蛋白尿的减少似乎是全身血压下降的结果。这些发现反对血管紧张素II在该模型中的特定作用。
结论
联合注射针对氨基肽酶A不同结构域的两个单抗在小鼠中引起大量的蛋白尿，这不仅仅依赖于血管紧张素II。我们假设单抗直接与氨基肽酶A上的至少两个致病结构域结合，触发足细胞释放与观察到的蛋白尿有关的介质。
BACKGROUND
Aminopeptidase A is an enzyme that is present on podocytes and is involved in the degradation of angiotensin II. In previous studies in mice, we administered single monoclonal antibodies directed against aminopeptidase A. We observed that only monoclonal antibodies that inhibited aminopeptidase A enzyme activity caused albuminuria.
METHODS
In this study, the effects of the combined injections of two monoclonal anti-aminopeptidase A antibodies (mAbs) were studied, using a combination of anti-aminopeptidase A mAbs that were directed against two different domains involved in the aminopeptidase A enzyme activity (ASD-3 or ASD-37) and an anti-aminopeptidase A mAb not related to the enzyme active site (ASD-41).
RESULTS
An injection of the combinations ASD-3/37 (total 4 mg, 1:1 ratio) and ASD-37/41 (total 4 mg, 1:1 ratio) in doses that do not cause albuminuria when given alone (4 mg) induced massive albuminuria at day 1 after injection. The combination ASD-3/41 had no effect. This albuminuria was not dependent on systemic immune mediators of inflammation and could not merely be related to a blockade of aminopeptidase A enzyme activity. However, a correlation was observed between the induction of albuminuria and the aggregation of the mAbs injected and aminopeptidase A on the podocytes. An injection of the combinations ASD-3/37 or ASD-37/41 did not cause an increase in systemic blood pressure. The treatment with a combination of enalapril and losartan lowered blood pressure (53 +/- 10 vs. 90 +/- 3 mm Hg in untreated mice) and reduced the acute albuminuria by 55% (11,145 +/- 864 vs. 24,517 +/- 2448 micrograms albumin/18 hr in untreated mice). However, similar effects were observed using triple therapy. Therefore, the reduction of albuminuria by the combined treatment of enalapril/losartan seems to be the consequence of the reduction in the systemic blood pressure. These findings argue against a specific role for angiotensin II in this model.
CONCLUSIONS
The combined injection of two mAbs directed against different domains of aminopeptidase A induces a massive albuminuria in mice, which is not merely dependent on angiotensin II. We hypothesize that the direct binding of mAbs to at least two pathogenic domains on aminopeptidase A triggers the podocyte to release mediators that are involved in the observed albuminuria.
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影响因子：
15.9
作者：
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DOI：
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发表时间：
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DOI：
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