Contribution of T lymphocytes in the development of maternal syndrome in Dahl SS rats

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PROJECT SUMMARY Contribution of T lymphocytes in the development of maternal syndrome in Dahl SS rats Preeclampsia (PE) is a pregnancy-specific disorder that is characterized by hypertension and proteinuria (maternal syndrome) developing after the 20th week of gestation. PE is the leading cause of maternal morbidity and mortality in the United States, affecting about 5% of pregnancies. Furthermore, women with preexisting hypertension or chronic kidney disease have an increased risk for developing PE. With rates of PE rising in the United States, the exact mechanism(s) responsible for the pathogenesis of the disease remain undetermined. The current hypothesis is thought to be a two-step process: 1) improper placentation and remodeling of the spiral arteries and 2) development of maternal syndrome. Current animal models require either a surgical or pharmacologic intervention to develop PE-like phenotypes; however, these models are not capable of investigating the first step in the disease process. An animal model that spontaneously develops PE is preferential to investigate the full course in the development of PE. Preliminary data demonstrate that the Dahl salt-sensitive (SS) rat is just such an animal model to help investigate mechanisms of PE since it spontaneously develops PE while remaining on a low salt (0.4% NaCl) diet. The present studies will test the general hypothesis that maternal syndrome in Dahl SS rats is an outcome of improper placentation resulting in an increased infiltration of T lymphocytes into kidney and placental tissues causing subsequent release of proinflammatory cytokines that contributes to the development hypertension and renal damage. To test this hypothesis, two specific aims are proposed. AIM 1 will first characterize the maternal syndrome phenotype in the Dahl SS rat on a low salt diet. To understand how T lymphocytes contribute to the pathogenesis, AIM 2 will explore the role of proinflammatory cytokine production due to infiltration of T lymphocytes into renal and placental tissue of Dahl SS rats. We have observed pregnancy- specific increases in blood pressure and proteinuria that are associated with increased infiltration of T lymphocytes into renal and placental tissues. This phenotype is consistent with what is observed in clinical settings, and this model provides a unique opportunity to study the whole disease process of PE. Completion of the studies in this proposal will establish a clear role for T lymphocytes in the pathogenesis of PE, and potentially uncover therapeutic targets to effectively treat PE.