title: PP085. Angiotensin II type 1 receptor antibodies increase angiotensin II sensitivity in pregnant rats.
abstract: BACKGROUND
  Pregnant women who subsequently develop preeclampsia are highly sensitive to infused angiotensin (Ang) II; the sensitivity persists postpartum. Activating autoantibodies against the Ang II type 1 (AT1) receptor are present in preeclampsia. In vitro and in vivo data suggest that they could be involved in the disease process.
  
  
  OBJECTIVE
  The aim of the study was to show if AT1-AB generated by immunisation alters Ang II sensitivity in pregnant rats.
  
  
  METHODS
  We generated and purified activating antibodies against the AT1 receptor (AT1-AB) by immunizing rabbits against the AFHYESQ epitope of the second extracellular loop, which is the binding epitope of endogenous activating autoantibodies against AT1 from patients with preeclampsia. We then purified AT1-AB using affinity chromatography with the AFHYESQ peptide.
  
  
  RESULTS
  We were able to detect AT1-AB both by ELISA and a functional bioassay. We then passively transferred AT1-AB into pregnant rats, alone or combined with Ang II. AT1-AB activated protein kinase C-alpha and extracellular-related kinase 1/2. Passive transfer of AT1-AB alone or Ang II (435ng/kg per minute) infused alone did not induce a preeclampsia-like syndrome in pregnant rats. However, the combination (AT1-AB plus Ang II) induced hypertension, proteinuria, intrauterine growth retardation, and arteriolosclerosis in the uteroplacental unit. We next performed gene-array profiling of the uteroplacental unit and found that hypoxia-inducible factor 1alpha was upregulated by Ang II plus AT1-AB, which we then confirmed by Western blotting in villous explants. Furthermore, endothelin 1 was upregulated in endothelial cells by Ang II plus AT1-AB. We show that AT1-AB induces Ang II sensitivity.
  
  
  CONCLUSIONS
  Our mechanistic study supports the existence of an "autoimmune-activating receptor" that could contribute to Ang II sensitivity and possibly to preeclampsia.
authors.affiliation: Experimental and Clinical Research Center, Medical Faculty of Charite, Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Wenzel
authors.affiliation: Experimental and Clinical Research Center, Max-Delbrueck Center for molecular Medicine, Berlin, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Herse
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, United States.
authors.forename: A
authors.initials: A
authors.lastname: Rajakumar
authors.affiliation: Max-Delbrueck Center for molecular Medicine, Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Haase
authors.affiliation: Magee-Womens Research Institute, Pittsburgh, United States.
authors.forename: C A
authors.initials: CA
authors.lastname: Hubel
authors.affiliation: Max-Delbrueck Center for molecular Medicine, Berlin, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Wallukat
authors.affiliation: Katholieken Universiteit Leuven, Leuven, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Pijnenborg
authors.affiliation: Experimental and Clinical Research Center, Max-Delbrueck Center for molecular Medicine, Berlin, Germany.
authors.forename: D N
authors.initials: DN
authors.lastname: Muller
authors.affiliation: Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, United States.
authors.forename: B B
authors.initials: BB
authors.lastname: LaMarca
authors.affiliation: Experimental and Clinical Research Center, HELIOS-Klinik, Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Dechend