title: Autoantibody-mediated IL-6-dependent endothelin-1 elevation underlies pathogenesis in a mouse model of preeclampsia.
abstract: Preeclampsia (PE) is a life-threatening hypertensive disorder of pregnancy. Elevated circulating endothelin-1 (ET-1) is associated with the disease. However the molecular basis of increased ET-1 production and its role in PE are unknown. This study aimed to investigate the causative factors, pathological role of elevated ET-1 production in PE, and the underlying mechanisms. In this study, we found that IgG from women with PE, in contrast to IgG from normotensive pregnant women, induced preproET-1 mRNA expression via angiotensin II type 1 receptor activation in kidneys and placentas in pregnant mice. The ET-A receptor-specific antagonist BQ123 significantly attenuated autoantibody-induced hypertension, proteinuria, and renal damage in pregnant mice, demonstrating that autoantibody-induced ET-1 production contributes to pathophysiology. Mechanistically, we discovered that IL-6 functioned downstream of TNF-α signaling, contributing to increased ET-1 production in pregnant mice. IL-6 blockade inhibited preeclamptic features in autoantibody-injected pregnant mice. Extending the data to human studies, we found that IL-6 was a key cytokine underlying ET-1 induction mediated by IgG from women with PE in human placental villous explants and that endothelial cells are a key source of ET-1. Overall, we provide human and mouse studies showing that angiotensin II type I receptor-agonistic autoantibody is a novel causative factor responsible for elevated ET-1 production and that increased TNF-α/IL-6 signaling is a key mechanism underlying increased ET-1 production and subsequent maternal features. Significantly, our findings revealed novel factors and signaling cascades involved in ET-1 production, subsequent disease symptom development, and possible therapeutic intervention in the management of PE.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Houston Medical School, Houston, TX 77030, USA.
authors.forename: Cissy Chenyi
authors.initials: CC
authors.lastname: Zhou
authors.forename: Roxanna A
authors.initials: RA
authors.lastname: Irani
authors.forename: Yingbo
authors.initials: Y
authors.lastname: Dai
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 / Q000276:immunology*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D051379:Mice; D010920:Placenta / Q000378:metabolism; D011225:Pre-Eclampsia / Q000276:immunology* / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D019332:Endothelin-1; D007074:Immunoglobulin G; D015850:Interleukin-6; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D014409:Tumor Necrosis Factor-alpha