Autoantibody-mediated angiotensin receptor activation contributes to preeclampsia through tumor necrosis factor-α signaling

Abstract

Preeclampsia is a prevalent life-threatening hypertensive disorder of pregnancy for which the pathophysiology remains largely undefined. Recently, a circulating maternal autoantibody, the angiotensin II type I (AT1) receptor agonistic autoantibody (AA), has emerged as a contributor to disease features. Increased circulating maternal tumor necrosis factor α (TNF-α) is also associated with the disease; however, it is unknown whether this factor directly contributes to preeclamptic symptoms. Here we report that this autoantibody increases the proinflammatory cytokine TNF-α in the circulation of AT1-AA-injected pregnant mice but not in nonpregnant mice. Coinjection of AT1-AA with a TNF-α neutralizing antibody reduced cytokine availability in AT1-AA-injected pregnant mice. Moreover, TNF-α blockade in AT1-AA-injected pregnant mice significantly attenuated the key features of preeclampsia. Autoantibody-induced hypertension was reduced from 131±4 to 110±4 mm Hg, and proteinuria was reduced from 212±25 to 155±23 μg of albumin per milligram of creatinine (both P<0.05). Injection of AT1-AA increased the serum levels of circulating soluble fms-like tyrosine kinase 1 and soluble endoglin (34.1±5.1, 2.4±0.3 ng/mL, respectively) and coinjection with the TNF-α blocker significantly reduced their levels (21.7±3.4 and 1.2±0.4 ng/mL, respectively). Renal damage and placental abnormalities were also decreased by TNF-α blockade. Lastly, the elevated circulating TNF-α in preeclamptic patients is significantly correlated with the AT1-AA bioactivity in our patient cohort. Similarly, the autoantibody, through AT1 receptor-mediated TNF-α induction, contributed to increased soluble fms-like tyrosine kinase 1, soluble endoglin secretion, and increased apoptosis in cultured human villous explants. Overall, AT1-AA is a novel candidate that induces TNF-α, a cytokine that may play an important pathogenic role in preeclampsia. Copyright © 2010 American Heart Association. All rights reserved.