Angiotensin II Type 1 Receptor Antibodies and Increased Angiotensin II Sensitivity in Pregnant Rats

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 58; no. 1; pp. 77 - 84
• Main Authors: Wenzel, Katrin, Rajakumar, Augustine, Haase, Hannelore, Geusens, Nele, Hubner, Norbert, Schulz, Herbert, Brewer, Justin, Roberts, Lyndsay, Hubel, Carl A, Herse, Florian, Hering, Lydia, Qadri, Fatimunnisa, Lindschau, Carsten, Wallukat, Gerd, Pijnenborg, Robert, Heidecke, Harald, Riemekasten, Gabriela, Luft, Friedrich C, Muller, Dominik N, Lamarca, Babette, Dechend, Ralf
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.07.2011; Lippincott Williams & Wilkins
• Subjects: Angiotensin II - genetics; Angiotensin II - metabolism; Animals; Arterial hypertension. Arterial hypotension; Autoantibodies; Biological and medical sciences; Blood and lymphatic vessels; Blotting, Western; Cardiology. Vascular system; Cells, Cultured; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Cricetinae; Enzyme-Linked Immunosorbent Assay; Female; Fetus - embryology; Fetus - metabolism; Gene Expression Regulation, Developmental; Medical sciences; Pre-Eclampsia - genetics; Pre-Eclampsia - immunology; Pre-Eclampsia - metabolism; Pregnancy; Pregnancy, Animal; Rabbits; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1 - immunology; Receptor, Angiotensin, Type 1 - metabolism; RNA - genetics; Hypertension; Pregnancy disorders; Rat; Peptide hormone; Rodentia; Cardiovascular disease; autoimmune disease; Pregnancy toxemia; Pregnancy; Octapeptide; Vertebrata; Mammalia; Immunology; Animal; Preeclampsia; Angiotensin II
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.111.171348

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. 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. 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-α and extracellular-related kinase 1/2. Passive transfer of AT1-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 (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 1α 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. Our mechanistic study supports the existence of an “autoimmune-activating receptor” that could contribute to Ang II sensitivity and possible to preeclampsia.