Inhibition of T‐cell activation attenuates hypertension,TNFα,IL‐17, and blood–brain barrier permeability in pregnant rats with angiogenic imbalance

Abstract

Problem Angiogenic imbalance during pregnancy is associated with immune activation, hypertension, increased T cell infiltration, and neurological insults. Method of Study On gestational day (GD) 12 timed-pregnant rats were infused with anti-angiogenic factors sFlt-1 and sEndoglin (4.7 and 7μg/kg) to create HELLP syndrome via mini-osmotic pumps for 8 days, with a subset of these rats having Orencia (2mg/kg) infused on GD13. On GD19, blood brain barrier (BBB) permeability was evaluated via Evan’s Blue infusion, blood was collected for T cell measurements, inflammatory cytokine secretion. Brain tissues were also collected to examine inflammatory cytokine infiltration. Results T cell attenuation with Orencia decreased circulating CD4+ and CD8+ T cells, circulating TNFα and IL-17, BBB permeability and significantly decreased biochemical evidence of HELLP compared to untreated HELLP rats. Conclusions These data support the hypothesis that T cells have a critical role in contributing to the pathophysiology that is seen in angiogenic imbalance during pregnancy.

Losartan, but not Enalapril and Valsartan, Inhibits the Expression of IFN-γ, IL-6, IL-17F and IL-22 in PBMCs from Rheumatoid Arthritis Patients

“…Accordingly, IL-17F appears as a target in Th17-mediated diseases such as RA [ 33 , 34 ]. That is interesting because although involved in RA, IL-17 also plays a key role in the pathogenesis of arterial hypertension, inducing the production of angiogenic factors and migration of endothelial cells [ 35 ]. IL-17A also mediates Angiotensin II (Ang II) induced renal injury and regulates renal sodium transporters, activating a serum and glucocorticoid regulated kinase 1 dependent pathway, and it could cause a sodium and water imbalance and therefore elevating the blood pressure [ 35 - 37 ].…”

Acute kidney injury during pregnancy leads to increased sFlt-1 and sEng and decreased renal T regulatory cells in pregnant rats with HELLP syndrome

“…On gestational day (GD) 12, mini-osmotic pumps (model 2002, Alzet Scientific Corporation, Cupertino, CA) were inserted into a subset of normal pregnant rats (NP) to allow infusion of sFlt-1 and sEng (4.7 and 7 μg/kg, respectively, R&D Systems, Minneapolis, MN) as previously described to induce the HELLP syndrome phenotype [ 15 , 16 , 20 ]. In the current study, we induced AKI by IR, since it has been reported to consistently induce AKI in experimental pregnant and non-pregnant animal models [ 21 , 22 ].…”

“…Soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) are anti-angiogenic proteins associated with preeclampsia and HELLP syndrome whose levels have been found to directly correlate with disease severity [ 13 , 14 ]. Furthermore, studies by our lab and others have reported that infusion or overexpression of sFlt-1 and sEng leads to the HELLP syndrome phenotype in pregnant rats [ 13 , 15 , 16 ]. Interestingly, sFlt-1 and sEng expression has been found to be increased in patients with chronic renal diseases and in experimental rodents following ischemia reperfusion (IR) [ 17 – 19 ].…”

Innate and Adaptive Immune Responses in HELLP Syndrome

“…In an experimental HELLP model obtained by chronic infusion of antiangiogenic factors, it was shown that the overall concentration of CD4+ and CD8+ T cells is increased, while Th17 and Treg concentrations were comparable between the groups (116,117). Later on, when these animals were treated with Abatacept, an antibody that blocks T cell activation, the biochemical parameters of HELLP syndrome were improved (118). However, the factor(s) leading to an increased T cell activation in HELLP, remains puzzling.…”