Autoantibody-Mediated Angiotensin Receptor Activation Contributes to Preeclampsia Through Tumor Necrosis Factor-α Signaling

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 (AT(1)) receptor agonistic autoantibody (AA), has emerged as a contributor to disease features. Increased circulating maternal tumor necrosis factor alpha (TNF-alpha) 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-alpha in the circulation of AT(1)-AA injected pregnant mice but not in nonpregnant mice. Coinjection of AT(1)-AA with a TNF-alpha neutralizing antibody reduced cytokine availability in AT(1)-AA-injected pregnant mice. Moreover, TNF-alpha blockade in AT(1)-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 mu g of albumin per milligram of creatinine (both P<0.05). Injection of AT(1)-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-alpha Mocker 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-alpha blockade. Lastly, the elevated circulating TNF-alpha in preeclamptic patients is significantly correlated with the AT(1)-AA bioactivity in our patient cohort. Similarly, the autoantibody, through AT(1) receptor-mediated TNF-alpha induction, contributed to increased soluble fms-like tyrosine kinase 1, soluble endoglin secretion, and increased apoptosis in cultured human villous explants. Overall, AT(1)-AA is a novel candidate that induces TNF-alpha, a cytokine that may play an important pathogenic role in preeclampsia. (Hypertension. 2010;55:1246-1253.)