CD4+ T Cells from RUPP rat model activate NK cells and cause mitochondrial oxidative stress and hypertension in normal pregnant rats

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Evangeline Deer ◽  
Kristin E. Reeve ◽  
Lorena M. Amaral ◽  
Venkata Ramana Vaka ◽  
Michael Franks ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
Nk Cells ◽  
Rat Model ◽  
Cd4 T Cells ◽  
Pregnant Rats ◽  
Mitochondrial Oxidative Stress

Abstract P225: Rupp Rat Model Cd4+ T Cells Activate Nk Cells And Cause Mitochondrial Oxidative Stress And Hypertension In Normal Pregnant Rats

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Evangeline M Deer ◽  
Kristin Reeve ◽  
Lorena M Amaral ◽  
Venkata Ramana Vaka ◽  
Michael Franks ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Rat Model ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Pregnant Rats ◽  
Atp Production

Preeclampsia (PE) is new onset hypertension during pregnancy and is associated with elevated inflammatory response such as CD4+ T cells, NK cells, and cytokines. We have previously shown women with PE exhibit increases in circulating and placental CD4+T cells and placental mitochondrial (mt) dysfunction/ROS compared to normal pregnant (NP) women. The Reduced Uterine Perfusion Pressure (RUPP) rat model produces many characteristics of PE such as hypertension, increases in CD4+ cells, increases in renal and placental NK cells, and mt dysfunction/ROS. We have previously demonstrated that RUPP CD4+T cells cause hypertension in NP rats, however the role of RUPP CD4+ T cells in stimulating NK cells to cause mt dysfunction/ROS are not elucidated. Therefore, we examined the effect of adoptive transfer of RUPP CD4+ T cells to activate NK cells in NP rats. Splenic CD4+ T cells were isolated from RUPP rats, cultured, and injected into NP rats on GD 13. On GD19, MAP values and blood/tissue samples were collected from both RUPP CD4+ T cell recipients and NP controls. Mitochondrial respiration and mtROS were measured in isolated mitochondria using the Oxygraph 2K and fluorescent microplate reader, respectively. A student’s t-test was used for statistical analysis. On GD19, MAP increased to 110±2 mmHg (n=13) in RUPP CD4+ T cell recipients compared to control NP rats 102±2 mmHg (n=7, p<0.05). Circulating cytolytic NK cells increased to 3±0.6% in RUPP CD4+ T cell recipients (n=8) compared to NP controls 0.3±0.2% (n=7, p<0.05). Placental state 3 (209.3±31.3 vs 422.7 ±83.3 pmol/sec/mg, p<0.05) and maximal (152.1±46.2 vs 229.7±58.9 pmol/sec/mg) and renal state 3 (133.4 ±21.4 vs 289.8±43.4 pmol/sec/mg, p<0.05) and maximal (61.8±18 vs 242.4±27.7 pmol/sec/mg, p<0.05) respiration rates, indicative of ATP production and electron transport chain efficacy respectively, were reduced with RUPP CD4+ T cells (n=6; n=9) compared to NP (n=5; n=5). Collectively, the data indicate that the adoptive transfer of RUPP CD4+ T cells stimulates cytolytic NK cells and placental and renal mitochondrial dysfunction/ROS during pregnancy as important mechanisms of hypertension in the pathophysiology of preeclampsia. Keywords: Preeclamspia, Hypertension, Oxidative stress

scholarly journals CD4+ T cells cause renal and placental mitochondrial oxidative stress as mechanisms of hypertension in response to placental ischemia

2021 ◽  
Vol 320 (1) ◽  
pp. F47-F54
Author(s):  
Evangeline Deer ◽  
Kristin E. Reeve ◽  
Lorena Amaral ◽  
Venkata Ramana Vaka ◽  
Michael Franks ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
T Cell ◽  
Mitochondrial Dysfunction ◽  
Nk Cells ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Mitochondrial Oxidative Stress ◽  
Uterine Perfusion ◽  
Placental Ischemia

The reduced uterine perfusion pressure (RUPP) rat model and normal pregnant (NP) rat recipients of RUPP CD4+ T cells recapitulate many characteristics of preeclampsia such as hypertension and oxidative stress. We have shown an important hypertensive role for natural killer (NK) cells to cause mitochondrial dysfunction in RUPP rats; however, the role for RUPP CD4+ T cells to stimulate NK cells is unknown. Therefore, we hypothesized that RUPP-induced CD4+ T cells activate NK cells to cause mitochondrial dysfunction/reactive oxygen species (ROS) as mechanisms of hypertension during pregnancy. We tested our hypothesis by adoptive transfer of RUPP CD4+ T cells into NP rats or by inhibiting the activation of RUPP CD4+ T cells with Orencia (abatacept) and examining hypertension, NK cells, and mitochondrial function. RUPP was performed on gestation day (GD) 14, and splenic CD4+ T cells were isolated on GD 19 and injected into NP rats on GD 13. In a separate group of rats, Orencia was infused and the RUPP procedure was performed. Mean arterial pressure and placental and renal mitochondrial ROS increased in RUPP ( n = 7, P < 0.05) and NP + RUPP CD4+ T-cell recipients ( n = 13, P < 0.05) compared with control NP ( n = 7) and NP + NP CD4+ T-cell recipients ( n = 5) but was reduced with Orencia ( n = 13, P < 0.05). Placental and renal respiration was reduced in RUPP ( n = 6, P < 0.05) and NP + RUPP CD4+ T-cell recipients ( n = 6, state 3 P < 0.05) compared with NP ( n = 5) and NP + NP CD4+ T-cell recipients ( n = 5) but improved with Orencia ( n = 9, n = 8 P < 0.05). These data indicate that CD4+ T cells, independent of NK cells, cause mitochondrial dysfunction/ROS contributing to hypertension in response to placental ischemia during pregnancy.

scholarly journals Characterization of Mitochondrial Bioenergetics in Preeclampsia

2021 ◽  
Vol 10 (21) ◽  
pp. 5063
Author(s):  
Ramana Vaka ◽  
Evangeline Deer ◽  
Mark Cunningham ◽  
Kristen M. McMaster ◽  
Kedra Wallace ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
Cd4 T Cells ◽  
Type I ◽  
Pregnant Rats ◽  
Complex Iv ◽  
Tnf Α ◽  
Placental Ischemia

Preeclampsia (PE) is characterized by new onset hypertension during pregnancy and is associated with oxidative stress, placental ischemia, and autoantibodies to the angiotensin II type I receptor (AT1-AA). Mitochondrial (mt) dysfunction in PE and various sources of oxidative stress, such as monocytes, neutrophils, and CD4 + T cells, have been identified as important players in the pathophysiology of PE. We have established the significance of AT1-AA, TNF-α, and CD4 + T cells in causing mitochondrial (mt) dysfunction in renal and placental tissues in pregnant rats. Although the role of mt dysfunction from freshly isolated intact placental mitochondria has been compared in human PE and normally pregnant (NP) controls, variations among preterm PE or term PE have not been compared and mechanisms contributing to mt ROS during PE are unclear. Therefore, we hypothesized PE placentas would exhibit impaired placental mt function, which would be worse in preterm PE patients than in those of later gestational ages. Immediately after delivery, PE and NP patient’s placentas were collected, mt were isolated and mt respiration and ROS were measured. PE patients at either < or >34 weeks gestational age (GA) exhibited elevated blood pressure and decreased placental mt respiration rates (state 3 and maximal). Patients delivering at >34 weeks exhibited decreased Complex IV activity and expression. Placental mtROS was significantly reduced in both PE groups, compared to NP placental mitochondria. Collectively, the study demonstrates that PE mt dysfunction occurs in the placenta, with mtROS being lower than that seen in NP controls. These data indicate why antioxidants, as a potential target or new therapeutic agent, may not be ideal in treating the oxidative stress associated with PE.

scholarly journals 24: NK cell-mediated mitochondrial oxidative stress and hypertension in response to CD4+T cells from RUPP rats

2020 ◽  
Vol 222 (1) ◽  
pp. S22
Author(s):  
Kristin E. Reeve ◽  
Evangeline Deer ◽  
Lorena M. Amaral ◽  
Venkata Ramana Vaka ◽  
Michael Franks ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
Cd4 T Cells ◽  
Nk Cell ◽  
Mitochondrial Oxidative Stress

scholarly journals HLA-E Up-Regulation Induced by HIV Infection May Directly Contribute to CD94-Mediated Impairment of NK Cells

2005 ◽  
Vol 18 (2) ◽  
pp. 269-276 ◽  
Author(s):  
F. Martini ◽  
C. Agrati ◽  
G. D'Offizi ◽  
F. Poccia
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Nk Cells ◽  
Cd4 T Cells ◽  
Nk Cell ◽  
Treatment Interruption ◽  
Cell Number ◽  
Hiv Replication

Alterations in NK cell numbers and function have been repeatedly shown during HIV infection. In this study, NK cell number and MHC class I expression on CD4+ T cells were studied in HIV patients at different stages of disease progression. An increased expression of HLA-E was seen on CD4+ T cells. In parallel, a reduced number of CD94+ NK cells was observed in advanced disease stages. Moreover, a decline in CD94 expression on NK cells was observed at the HIV replication peak in patients undergoing antiretroviral treatment interruption, suggesting a role of viral replication on NK cells alterations. In vitro HIV infection induced a rapid down-regulation of HLA-A,B,C expression, paralleled by an increased expression of HLA-E surface molecules, the formal ligands of CD94 NK receptors. HIV-infected HLA-E expressing cells were able to inhibit NK cell cytotoxicity through HLA-E expression, since cytotoxicity was restored by antibody masking experiments. These data indicate that the CD94/HLA-E interaction may contribute to NK cell dysfunction in HIV infection, suggesting a role of HIV replication in this process.

scholarly journals Erratum: A TLR7 agonist enhances the antitumor efficacy of obinutuzumab in murine lymphoma models via NK cells and CD4 T cells

Leukemia ◽  
2017 ◽  
Vol 31 (10) ◽  
pp. 2278-2278 ◽  
Author(s):  
E J Cheadle ◽  
G Lipowska-Bhalla ◽  
S J Dovedi ◽  
E Fagnano ◽  
C Klein ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Cd4 T Cells ◽  
Antitumor Efficacy ◽  
Murine Lymphoma ◽  
Tlr7 Agonist

Astragaloside IV ameliorates preeclampsia-induced oxidative stress through the Nrf2/HO-1 pathway in a rat model

2020 ◽  
Vol 319 (5) ◽  
pp. E904-E911 ◽  
Author(s):  
Shuangyan Yang ◽  
Ruixue Zhang ◽  
Baoheng Xing ◽  
Ling Zhou ◽  
Peipei Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Rat Model ◽  
Target Genes ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Astragaloside Iv ◽  
Pregnant Rats ◽  
Beneficial Effects ◽  
Antioxidative Effects ◽  
Protein Serum

Preeclampsia (PE) can cause serious health problems for pregnant women and their infants. Astragaloside IV has been shown to exert cardioprotective, anti-inflammatory, and antioxidative effects on various disorders. We aimed to study the effects of Astragaloside IV on PE symptoms using an NG-nitro-l-arginine methyl ester (l-NAME)-induced rat model of PE. The pregnant rats’ physiological features, including blood pressure, urine protein, serum soluble fms-like tyrosine kinase- 1 ( sFlt - 1)/placental growth factor (PlGF) ratio, and weight of placenta, as well as the weight, length, and survival of pups, were documented. The expression levels of target genes were analyzed by Western blot and qRT-PCR assays. The levels of target secreted proteins were determined by ELISA. We demonstrated that the administration of Astragaloside IV might exert a multitude of beneficial effects on attenuated PE symptoms in a rat model of PE. We further revealed that the effects of Astragaloside IV on PE rats were achieved, at least partially, through elimination of oxidative stress and stimulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. Our study indicated that Astragaloside IV may serve as a promising candidate for the development of new therapeutic methods for patients with PE.

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