title: Autoantibody-mediated angiotensin receptor activation contributes to preeclampsia through tumor necrosis factor-alpha 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 (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 microg 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 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-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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Houston Medical School, 6431 Fannin St, Houston, TX 77030, USA.
authors.forename: Roxanna A
authors.initials: RA
authors.lastname: Irani
authors.forename: Yujin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Cissy Chenyi
authors.initials: CC
authors.lastname: Zhou
authors.forename: Sean C
authors.initials: SC
authors.lastname: Blackwell
authors.forename: M John
authors.initials: MJ
authors.lastname: Hicks
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ramin
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000502:physiology*; D002585:Cesarean Section; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D011225:Pre-Eclampsia / Q000276:immunology / Q000503:physiopathology* / Q000517:prevention & control; D011247:Pregnancy; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology / Q000502:physiology*; D012016:Reference Values; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*
chemical_list: D001323:Autoantibodies; D044140:Receptor, Angiotensin, Type 1; D014409:Tumor Necrosis Factor-alpha