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 agonistic
autoantibody, which emerged recently as a potential pathogenic contributor to PE, stimulates deposition of
complement C3 in placentas and kidneys of pregnant mice via
angiotensin II type 1 receptor activation. Next, we provide in vivo evidence that selectively interfering with C3a signaling by a
complement C3a receptor-specific antagonist significantly reduces
hypertension from 167±7 to 143±5 mm Hg and
proteinuria from 223.5±7.5 to 78.8±14.0 μg of
albumin per milligram
creatinine (both P<0.05) in
angiotensin II type 1 receptor agonistic
autoantibody-injected pregnant mice. In addition, we demonstrated that
complement C3a receptor antagonist significantly inhibited
autoantibody-induced circulating soluble
fms-like tyrosine kinase 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 with normotensive controls. Lastly, we show that
complement C3a receptor activation is a key mechanism underlying
autoantibody-induced soluble
fms-like tyrosine kinase 1 secretion and decreased angiogenesis in cultured human villous explants. Overall, we provide mouse and human evidence that
angiotensin II type 1 receptor agonistic
autoantibody-mediated activation contributes to elevated C3 and that
complement C3a receptor signaling is a key mechanism underlying the pathogenesis of the disease. These studies are the first to link
angiotensin II type 1 receptor agonistic
autoantibody with complement activation and to provide important new opportunities for therapeutic intervention in PE.