Classical Complement Pathway Activation in the Kidneys of Women With Preeclampsia.
Classical Complement Pathway Activation in the Kidneys of Women With Preeclampsia.
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DOI：
10.1161/hypertensionaha.115.05484
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发表时间：
2015-07
期刊：
影响因子：
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通讯作者：
Baelde H
中科院分区：
文献类型：
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作者：
Penning M;Chua JS;van Kooten C;Zandbergen M;Buurma A;Schutte J;Bruijn JA;Khankin EV;Bloemenkamp K;Karumanchi SA;Baelde H
越来越多的证据表明，补体失调在先兆子痫的发病机制中起作用。肾脏是先兆子痫的主要器官之一。由于肾脏对补体激活高度敏感，我们假设先兆子痫与肾脏补体激活有关。我们使用计算机数据库（PALGA）在荷兰进行了一次全国性的肾脏尸检材料检索。肾组织取自11名先兆子痫妇女、25名妊娠对照和14名非妊娠高血压对照。对样本进行C4d、C1 q、MBL、备解素、C3 d、C5 b-9、伊加、IgG和IgM免疫染色。先兆子痫与肾C4d（补体激活的稳定标志物）和经典途径标志物C1 q显著相关。此外，IgM的患病率在先兆子痫妇女的肾脏中显著更高。研究的其他补体标志物在组间无差异。我们在人类样本中的发现是使用可溶性fms样酪氨酸激酶1（sFlt-1）先兆子痫小鼠模型进行验证的。注射sFlt-1的小鼠的肾脏比对照小鼠具有显著更多的C4沉积。先兆子痫与肾脏C4d、C1 q和IgM水平之间的相关性表明经典补体途径参与了先兆子痫的肾脏损伤。此外，我们发现sFlt-1注射小鼠产生过量的C4沉积，表明血管生成失调可能在肾脏内的补体激活中起作用。我们认为，抑制补体激活可能有利于预防先兆子痫的肾脏表现。
A growing body of evidence suggests that complement dysregulation plays a role in the pathogenesis of preeclampsia. The kidney is one of the major organs affected in preeclampsia. Because the kidney is highly susceptible to complement activation, we hypothesized that preeclampsia is associated with renal complement activation. We performed a nationwide search for renal autopsy material in the Netherlands using a computerized database (PALGA). Renal tissue was obtained from 11 women with preeclampsia, 25 pregnant controls, and 14 non-pregnant controls with hypertension. The samples were immunostained for C4d, C1q, MBL, properdin, C3d, C5b-9, IgA, IgG, and IgM. Preeclampsia was significantly associated with renal C4d—a stable marker of complement activation—and the classical pathway marker C1q. In addition, the prevalence of IgM was significantly higher in the kidneys of the preeclamptic women. No other complement markers studied differed between the groups. Our findings in human samples were validated using a soluble fms-like tyrosine kinase 1 (sFlt-1) mouse model of preeclampsia. The kidneys in the sFlt-1–injected mice had significantly more C4 deposits than the control mice. The association between preeclampsia and renal C4d, C1q, and IgM levels suggests that the classical complement pathway is involved in the renal injury in preeclampsia. Moreover, our finding that sFlt-1–injected mice develop excess C4 deposits indicates that angiogenic dysregulation may play a role in complement activation within the kidney. We suggest that inhibiting complement activation may be beneficial for preventing the renal manifestations of preeclampsia.