Honors Theses

Date of Award

Spring 5-4-2022

Document Type

Undergraduate Thesis



First Advisor

Colin Jackson

Second Advisor

Carol Britson

Third Advisor

Robert Brian Doctor

Relational Format



Preeclampsia (PE) is a disease characterized by new-onset hypertension in the third trimester of pregnancy, endothelial dysfunction, and placental ischemia. Contributory to these characteristics are circulating factors such as agonistic autoantibodies to the angiotensin I type II receptor (AT1-AA), CD4+ T cells, natural killer cells (NK), and oxidative stress, which I will show to contribute to renal and placental mitochondrial dysfunction during pregnancy. The adoptive transfer of CD4+ T cells from the Reduced Uterine Perfusion Pressure (RUPP) rat model of PE to a healthy normal pregnant rat has been shown to result in many of these characteristics, including AT1-AA production. In addition, an important hypertensive role for NK cells to cause mitochondrial dysfunction in RUPP rats has also been shown. Moreover, studies show that inhibition of AT1-AA activity ameliorates hypertensive and inflammatory characteristics of the RUPP model; however, what is not known is the contributory role of RUPP CD4+ T cells to NK cell activation via AT1-AAs causing mitochondrial dysfunction as a mechanism of hypertension during pregnancy. Therefore, I hypothesized that RUPP-induced mitochondrial dysfunction/reactive oxygen species (ROS) act as mechanisms of hypertension during pregnancy that are mediated by AT1-AA induced NK cells, which is orchestrated through the activation of CD4+T cells, eliciting a long-term memory B cell response in pregnant mothers with PE. This experiment aimed to test these hypotheses: 1) activation of CD4+ T cells in RUPP rats causes NK cell mediated mitochondrial (MT) oxidative stress, and 2) inhibition of AT1-AA activity lowered NK cell activation and mt dysfunction in the RUPP rat model of PE. To observe the role of CD4+ T cells in NK cell activation and oxidative stress, adoptive transfer was performed, and resultant NK cell levels, mitochondrial dysfunction, and oxidative stress were measured. In addition, CD4+T cells were experimentally inhibited by infusion of Orencia (abatacept) and resultant NK cell levels, mitochondrial dysfunction, and oxidative stress were measured. In order to test hypothesis 2, a novel peptide (‘n7AAc’) that prevents binding of AT1-AAs to their receptor was given to a separate group of RUPP rats via mini osmotic pump, and NK Cells, mitochondrial function and oxidative stress was measured. Oxidative stress, NK cell activation, and mitochondrial dysfunction were all elevated in RUPP rats, as well as RUPP T cell recipients. Inhibition of either CD4+ T cells or AT1-AA in RUPP rats improved mitochondrial function and NK cell activity and blood pressure. In conclusion, NK cells’ cytolytic activity, as a result of AT1-AA release that is originally stimulated by CD4+ T cell to B cell communication, plays an important role in the pathophysiology of PE.

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