title: Activating autoantibodies to the angiotensin II type I receptor play an important role in mediating hypertension in response to adoptive transfer of CD4+ T lymphocytes from placental ischemic rats.
abstract: Hypertension in rats with chronic placental ischemia (reduced uterine perfusion pressure, RUPP) is associated with elevated inflammatory cytokines, agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) and CD4(+) T cells; all of which are elevated in preclamptic women. Additionally, we have shown that adoptive transfer of RUPP CD4(+) T cells increases blood pressure, inflammatory cytokines, and sFlt-1. The objective of this study was to determine the long-term effects of RUPP CD4(+) T cells on AT1-AA, renal and systemic hemodynamics in pregnant rats. To answer this question CD4(+) T splenocytes were magnetically isolated on day 19 of gestation from control RUPP and normal pregnant (NP) rats and injected into a new group of NP rats at day 13 of gestation. On day 19 of gestation mean arterial pressure (MAP) and renal function (glomerular filtration rates, GFR) were analyzed and serum collected for AT1-AA analysis. To determine a role for AT1-AA to mediate RUPP CD4(+) T cell-induced blood pressure increases, MAP was analyzed in a second group of rats treated with AT1 receptor blockade losartan (10 mg·kg(-1)·day(-1)) and in a third group of rats treated with rituximab, a B cell-depleting agent (250 mg/kg) we have shown previously to decrease AT1-AA production in RUPP rats. MAP increased from 101 ± 2 mmHg NP to 126 ± 2 mmHg in RUPP rats (P < 0.001) and to 123 ± 1 mmHg in NP rats injected with RUPP CD4(+) T cells (NP+RUPP CD4(+)T cells) (P < 0.001). Furthermore, GFR decreased from 2.2 ml/min (n = 7) in NP rats to 1.0 ml/min (n = 5) NP+RUPP CD4(+)T cell. Circulating AT1-AA increased from 0.22 ± 0.1 units in NP rats to 13 ± 0.7 (P < 0.001) units in NP+RUPP CD4(+)T cell-treated rats but decreased to 8.34 ± 1 beats/min in NP+RUPP CD4(+) T cells chronically treated with rituximab. Hypertension in NP+RUPP CD4(+)T cell group was attenuated by losartan (102 ± 4 mmHg) and with B cell depletion (101 ± 5 mmHg). Therefore, we conclude that one mechanism of hypertension in response to CD4(+) T lymphocytes activated during placental ischemia is via AT1 receptor activation, potentially via AT1-AA during pregnancy.
authors.affiliation: Department of Obstetricsand Gynecology, University of Mississippi Medical Center, Jackson, Mississippi 39216-4505, USA.
authors.forename: Sarah Richards
authors.initials: SR
authors.lastname: Novotny
authors.forename: Kedra
authors.initials: K
authors.lastname: Wallace
authors.forename: Judith
authors.initials: J
authors.lastname: Heath
authors.forename: Janae
authors.initials: J
authors.lastname: Moseley
authors.forename: Pushpinder
authors.initials: P
authors.lastname: Dhillon
authors.forename: Abram
authors.initials: A
authors.lastname: Weimer
authors.forename: Gerd
authors.initials: G
authors.lastname: Wallukat
authors.forename: Florian
authors.initials: F
authors.lastname: Herse
authors.forename: Katrin
authors.initials: K
authors.lastname: Wenzel
authors.forename: James N
authors.initials: JN
authors.lastname: Martin
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
authors.forename: Babbette
authors.initials: B
authors.lastname: Lamarca
mesh_terms: D019264:Adoptive Transfer; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology / Q000637:transplantation*; D004461:Eclampsia / Q000276:immunology / Q000503:physiopathology; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000276:immunology / Q000503:physiopathology*; D007511:Ischemia / Q000503:physiopathology*; D007668:Kidney / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D023421:Models, Animal; D010920:Placenta / Q000098:blood supply*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000276:immunology*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001323:Autoantibodies; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan