title: Role of IgM and angiotensin II Type I receptor autoantibodies in local complement activation in placental ischemia-induced hypertension in the rat.
abstract: Preeclampsia is characterized by development of hypertension during pregnancy and reduced placental perfusion. Previous studies in a rat model of placental ischemia-induced hypertension demonstrated that inhibiting complement activation attenuated increased maternal blood pressure with C3a and C5a identified as the important products of complement activation. Given that in other forms of ischemia both natural IgM and antigen antibody complexes initiate complement activation, we hypothesized that placental ischemia exposes neoepitopes recognized by IgM to cause local complement activation and hypertension. Alternatively, we postulated that autoantibody to angiotensin II Type 1 receptor (AT1-AA) interacts with AT1 receptors to cause complement activation. Since complement activation occurs in kidney and placenta in preeclampsia, we used immunohistochemistry to determine IgM deposition and local complement activation in each organ (C3 deposition), and quantitative real-time polymerase chain reaction (qRT-PCR) to quantitate mRNA for endogenous regulators of complement activation CD55, CD59 and Complement receptor 1-related gene/protein y (Crry). On gestation day (GD)14.5, timed pregnant Sprague Dawley rats underwent Sham surgery or placement of clips on inferior abdominal aorta and ovarian arteries to create placental ischemia using the reduced utero-placental perfusion pressure (RUPP) model. As previously reported, RUPP surgery increased mean arterial pressure and circulating C3a on GD19.5. In placenta, IgM and C3 deposition increased, whereas mRNA for complement regulators Crry and CD59 decreased along with Crry protein in RUPP compared to Sham treated animals. In kidney, IgM deposition increased in animals subjected to RUPP vs Sham surgery without a significant change in C3 deposition and coincident with an increase in mRNA for CD55 and CD59. The AT1 receptor antagonist losartan prevents placental ischemia-induced hypertension as well as AT1-AA interaction with AT1 receptors. However, losartan did not attenuate complement activation as measured by circulating C3a or placental C3 deposition. Importantly, our studies indicate that following placental ischemia, complement activation is not due to AT1-AA but is associated with IgM deposition. These studies suggest a role for natural antibodies interacting with placental ischemia-induced neoepitopes to activate complement and contribute to hypertension.
authors: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth campus, Duluth, MN, United States. Electronic address: jregal@d.umn.edu.
authors: Jean F
authors: JF
authors: Regal
authors: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth campus, Duluth, MN, United States. Electronic address: streh036@d.umn.edu.
authors: Megan E
authors: ME
authors: Strehlke
authors: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth campus, Duluth, MN, United States. Electronic address: jenna-peterson-1@uiowa.edu.
authors: Jenna M
authors: JM
authors: Peterson
authors: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth campus, Duluth, MN, United States. Electronic address: wing0155@umn.edu.
authors: Cameron R
authors: CR
authors: Wing
authors: Division of Biology, Kansas State University, Manhattan, KS, United States. Electronic address: j.elizabeth.parker@gmail.com.
authors: Jordan E
authors: JE
authors: Parker
authors: Division of Biology, Kansas State University, Manhattan, KS, United States. Electronic address: nieto@ksu.edu.
authors: Noel Fernando
authors: NF
authors: Nieto
authors: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth campus, Duluth, MN, United States. Electronic address: ltbemis@d.umn.edu.
authors: Lynne T
authors: LT
authors: Bemis
authors: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth campus, Duluth, MN, United States. Electronic address: jgilbert@d.umn.edu.
authors: Jeffrey S
authors: JS
authors: Gilbert
authors: Division of Biology, Kansas State University, Manhattan, KS, United States. Electronic address: sdflemin@ksu.edu.
authors: Sherry D
authors: SD
authors: Fleming
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D003167:Complement Activation / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006973:Hypertension / Q000276:immunology*; D007075:Immunoglobulin M; D007150:Immunohistochemistry; D007511:Ischemia / Q000150:complications; D010920:Placenta / Q000098:blood supply; D011225:Pre-Eclampsia / Q000276:immunology* / Q000503:physiopathology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D007075:Immunoglobulin M; D044140:Receptor, Angiotensin, Type 1
keywords: Autoantibody; C3 deposition; Complement; Natural antibody; Preeclampsia; Pregnancy-induced hypertension