title: Autoantibody-mediated complement C3a receptor activation contributes to the pathogenesis of preeclampsia.
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 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.
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Hunan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Roxanna A
authors.initials: RA
authors.lastname: Irani
authors.forename: Yujin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ramin
authors.forename: Sean C
authors.initials: SC
authors.lastname: Blackwell
authors.forename: Lijian
authors.initials: L
authors.lastname: Tao
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000378:metabolism*; D016022:Case-Control Studies; D002824:Chorionic Villi / Q000378:metabolism; D003176:Complement C3 / Q000378:metabolism; D005260:Female; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010920:Placenta / Q000378:metabolism; D011225:Pre-Eclampsia / Q000209:etiology* / Q000378:metabolism*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000209:etiology* / Q000378:metabolism*; D011270:Pregnancy, Animal / Q000378:metabolism*; D011507:Proteinuria / Q000209:etiology / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D011951:Receptors, Complement / Q000378:metabolism*; D046509:Tissue Culture Techniques; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D003176:Complement C3; D044140:Receptor, Angiotensin, Type 1; D011951:Receptors, Complement; C085567:complement C3a receptor; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1