Mechanisms of Cardiorenal Disease following Preeclampsia

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Preeclampsia is one of the leading causes of maternal morbidity and death worldwide today, affecting approximately 5% of all pregnancies in the United States. Preeclampsia is characterized by hypertension during the second half of pregnancy and progressive development of proteinuria, along with systemic endothelial dysfunction. The risk to the mother does not end with delivery of the fetoplacental unit however. Women who experience preeclampsia have a heightened risk for hypertension, stroke, heart disease, and kidney disease, but the mechanisms that contribute to cardiovascular and renal disease following preeclampsia are unclear. Therefore, there is a vital need for the determination of optimal therapeutic regimens for women following preeclampsia. Unfortunately, the lack of a spontaneous animal model of preeclampsia has been an obstacle in the identification of the mechanisms and potential therapeutic targets during and following preeclampsia. Our exciting preliminary data show that the Dahl Salt Sensitive (Dahl S) rat spontaneously develops characteristics of preeclampsia during pregnancy that are similar to the human disease and has accelerated cardiorenal disease and immune activation that persists postpartum. This model will allow us to significantly advance our knowledge by examining the long-term impact of preeclamptic pregnancy on endothelial function, progression of kidney disease, and immune activation in females with pre-existing hypertension and determine if intensive perinatal management of blood pressure will improve long term cardiovascular health outcomes. This project will test the central hypothesis that preeclampsia results in a lasting postpartum immunological activation that predisposes the mother to progression of endothelial dysfunction and CKD. This research will have a significant impact on the field by 1) providing an understanding of mechanisms that contribute to the long term increased risk of cardiorenal disease following preeclamptic pregnancy and 2) providing preclinical studies to inform decisions regarding the perinatal care for women at risk of developing preeclampsia. Therefore, this work has important clinical and translational value as these findings could ultimately help us identify novel therapeutic targets to improve outcomes for women with a history of preeclampsia and identify treatment regimens to attenuate the long term risk of cardiovascular death in these women.