Role of the prostaglandin E2 receptor EP1 in hypertensive end-organ damage
Bartlett, Christina Swan
Hypertension is a prevalent disease affecting one in three adults in the United States. Approximately 25 % of the adult population is either not receiving therapy for their hypertension or is unable to control their blood pressure with current therapies, making treatment of hypertension an important public health goal. In blood pressure regulation, PGE2 can act in a pro-hypertensive or anti-hypertensive manner. It has been demonstrated that EP2 and EP4 receptors mediate the vasodepressor actions of PGE2 and EP1 and EP3 receptors mediate the vasopressor actions of PGE2. Additionally, PGE2 and the EP1 receptor have been demonstrated to mediate at least part of the actions of angiotensin II. I sought to determine the contribution of EP1 and/or EP3 receptors to hypertensive end-organ damage and diabetic nephropathy. In this dissertation, I utilize mice with genetic disruption of EP1 or EP3 receptors and characterize the outcomes of several models of hypertensive organ damage. In the Nphx/DOCA-NaCl/Ang II model of hypertension, I have demonstrated that disruption of EP1 or EP3 can afford substantial protection from end-organ damage and reduce incidence of mortality. The beneficial effects of EP1 disruption, and likely EP3 disruption, appear to be a result of reduction in MAP in this model. The use of another model involving uninephrectomy and Ang II on a 129S6 background suggests the EP1 receptor plays an important role in hypertensive renal disease independent of blood pressure reduction. Furthermore, genetic disruption of EP1 protected eNOS-/- mice from diabetes-induced proteinuria, independent of blood pressure reduction. In summary, the data presented in this dissertation advances our knowledge of the role of EP1 and EP3 receptors in hypertension and subsequent sequalae and demonstrate a detrimental role of EP1 in this disease. Targeting the EP1 receptor may be a viable pharmaceutical treatment strategy for hypertension and subsequent organ damage.