The role of T cell stimulated agonistic autoantibodies to the angiotensin II type I receptor (AT1‐AA) in mediating multiorgan dysfunction in IL‐17 induced hypertension during pregnancy

Abstract

AbstractProblemPreeclampsia (PE), new‐onset hypertension during pregnancy accompanied by organ dysfunction, is associated with chronic inflammation including elevated IL‐17, CD4+ T cells, B cells and natural killer (NK) cells. IL‐17 can serve as a signal for either the adaptive or innate immune activation. We have previously shown that IL‐17 contributes to increased blood pressure in association with elevated TH17 cells, NK cells and B cells secreting angiotensin II type 1 receptor agonistic autoantibodies (AT1‐AA) during pregnancy. Moreover, we have shown an important role for CD4+T cells and AT1‐AA in multiorgan dysfunction as measured by mitochondrial oxidative stress (mt ROS). However, we do not know the role of adaptive immune cells such as T cells or B cells secreting AT1‐AA in mediating the PE phenotype in response to elevated IL‐17.Method of studyIn order to answer this question, we infused IL‐17 (150 pg/day i.p.) into either Sprague Dawley (SD) or athymic nude rats via mini‐osmotic pump from gestational day (GD) 14–19 of pregnancy. On GD 19, blood pressure was determined and NK cells, mtROS and respiration and AT1‐AA production from B cells were measured.ResultsInfusion of IL‐17 increased blood pressure in the presence or absence of T cells. Mean arterial pressure (MAP) increased with IL‐17 from 98 ± 2 mm Hg (n = 12) to 114 ± 2 (n = 12) in SD rats and from 99 ± 4 mm Hg (n = 7) versus 115 ± 2 mm Hg (n = 7) in athymic nude rats. Similar trends were seen in NK cells and placental mt ROS. Knowing that IL‐17 stimulates AT1‐AA in SD pregnant rats, we included a group of SD and athymic nude pregnant rats infused with IL‐17 and the AT1‐AA inhibitor peptide (‘n7AAc’). The inhibitor attenuated blood pressure (104.9 ± 3.2, p = .0001) and normalized NK cells and mt function in SD pregnant rats. Importantly, the AT1‐AA was not produced in pregnant nude IL‐17 treated rats, nor did ‘n7AAc’ effect MAP, in nude athymic rats.ConclusionThese findings suggest two conclusions; one is that IL‐17 causes hypertension and multiorgan dysfunction in the absence of T cells and AT1‐AA, possibly through its activation of innate cells and secondly, in the presence of T cells, blockade of the AT1‐AA attenuates the effect of IL‐17. This study indicates the critical effects of elevated IL‐17 during pregnancy and suggest treatment modalities to consider for PE women.