title: Angiotensin II type 1 receptor antibodies and increased angiotensin II sensitivity in pregnant rats.
abstract: 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 (AT(1)) receptor are present in preeclampsia. In vitro and in vivo data suggest that they could be involved in the disease process. We generated and purified activating antibodies against the AT(1) receptor (AT(1)-AB) by immunizing rabbits against the AFHYESQ epitope of the second extracellular loop, which is the binding epitope of endogenous activating autoantibodies against AT(1) from patients with preeclampsia. We then purified AT(1)-AB using affinity chromatography with the AFHYESQ peptide. We were able to detect AT(1)-AB both by ELISA and a functional bioassay. We then passively transferred AT(1)-AB into pregnant rats, alone or combined with Ang II. AT(1)-AB activated protein kinase C-α and extracellular-related kinase 1/2. Passive transfer of AT(1)-AB alone or Ang II (435 ng/kg per minute) infused alone did not induce a preeclampsia-like syndrome in pregnant rats. However, the combination (AT(1)-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 1α was upregulated by Ang II plus AT(1)-AB, which we then confirmed by Western blotting in villous explants. Furthermore, endothelin 1 was upregulated in endothelial cells by Ang II plus AT(1)-AB. We show that AT(1)-AB induces Ang II sensitivity. Our mechanistic study supports the existence of an "autoimmune-activating receptor" that could contribute to Ang II sensitivity and possible to preeclampsia.
authors.affiliation: Medical Faculty of the Charité, Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Wenzel
authors.forename: Augustine
authors.initials: A
authors.lastname: Rajakumar
authors.forename: Hannelore
authors.initials: H
authors.lastname: Haase
authors.forename: Nele
authors.initials: N
authors.lastname: Geusens
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.forename: Herbert
authors.initials: H
authors.lastname: Schulz
authors.forename: Justin
authors.initials: J
authors.lastname: Brewer
authors.forename: Lyndsay
authors.initials: L
authors.lastname: Roberts
authors.forename: Carl A
authors.initials: CA
authors.lastname: Hubel
authors.forename: Florian
authors.initials: F
authors.lastname: Herse
authors.forename: Lydia
authors.initials: L
authors.lastname: Hering
authors.forename: Fatimunnisa
authors.initials: F
authors.lastname: Qadri
authors.forename: Carsten
authors.initials: C
authors.lastname: Lindschau
authors.forename: Gerd
authors.initials: G
authors.lastname: Wallukat
authors.forename: Robert
authors.initials: R
authors.lastname: Pijnenborg
authors.forename: Harald
authors.initials: H
authors.lastname: Heidecke
authors.forename: Gabriela
authors.initials: G
authors.lastname: Riemekasten
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Muller
authors.forename: Babette
authors.initials: B
authors.lastname: Lamarca
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
mesh_terms: D000804:Angiotensin II / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001323:Autoantibodies; D015153:Blotting, Western; D002478:Cells, Cultured; D006224:Cricetinae; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005333:Fetus / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D011225:Pre-Eclampsia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal; D012313:RNA / Q000235:genetics*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D012313:RNA