NDLI: Autoantibody-mediated complement C3a receptor activation contributes to the pathogenesis of preeclampsia

Content Provider	PubMed Central
Author	Wang, Wei Irani, Roxanna A. Zhang, Yujin Ramin, Susan M. Blackwell, Sean C. Tao, Lijian Kellems, Rodney E. Xia, Yang
Abstract	Preeclampsia (PE) is a prevalent life-threatening hypertensive disorder of pregnancy associated with increased complement activation. However, the causative factors and pathogenic role of increased complement activation in PE are largely unidentified. Here we report that a circulating maternal autoantibody, the angiotensin II type 1 receptor (AT1R) agonistic autoantibody (AT1-AA), recently emerged as a potential pathogenic contributor to PE, stimulates deposition of complement C3 in placentas and kidneys of pregnant mice via AT1R activation. Next, we provide in vivo evidence that selectively interfering with C3a signaling by C3a receptor (C3aR) specific antagonist significantly reduces hypertension from 167±7 to 143±5 mmHg and proteinuria from 223.5±7.5 to 78.8 ± 14.0 µg albumin/mg creatinine (both P<0.05) in AT1-AA-injected pregnant mice. Additionally, we demonstrated that C3aR antagonist significantly inhibited autoantibody-induced circulating soluble fms-like tyrosine kinase-1 (sFlt-1), a known antiangiogenic protein associated with PE, and reduced small placental size with impaired angiogenesis and intrauterine growth restriction. Similarly, in humans, we demonstrate that C3 deposition is significantly elevated in the placentas of preeclamptic patients compared to normotensive controls. Lastly, we show that C3aR activation is a key mechanism underlying autoantibody-induced sFlt-1 secretion and decreased angiogenesis in cultured human villous explants. Overall, we provide mouse and human evidence that AT1-AA-mediated AT1R activation contributes to elevated C3 and that C3aR signaling is a key mechanism underlying the pathogenesis of the disease. These studies are the first to link AT1-AA with complement activation and provide important new opportunities for therapeutic intervention in PE.
Related Links	http://dx.doi.org/10.1161/hypertensionaha.112.191817
Ending Page	721
Page Count	10
Starting Page	712
File Format	PDF
ISSN	0194911X
e-ISSN	15244563
Journal	Hypertension
Issue Number	3
Volume Number	60
Language	English
Publisher Date	2012-09-01
Access Restriction	Open
Subject Keyword	Internal Medicine Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Internal Medicine

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