The studies proposed in the present application are designed to evaluate the role of platelet-activating factor as a mediator of the renal pathophysiology associated with preeclampsia. Preeclampsia (PE) is a pregnancy-associated disease which affects the well-being of both mother and fetus, and is a leading cause of perinatal morbidity and mortality. While the physiological mechanisms underlying this disorder remain poorly understood, it is strongly suggested that PE may be associated with endothelial cell damage which results in altered production of a number of endothelial vasoactive factors, including endothelin-1 (ET-1). The presently proposed studies will use a newly developed model of elevated circulating ET-1 in pregnant sheep in which chronic, low-level infusion of ET-1 produces a PE-like syndrome, i.e. proteinuria, reduced uterine blood flow, reduced intravascular volume, and mild/moderate hypertension. The development of this model was based on reported evidence that plasma ET-1 is elevated in clinical PE. Interestingly, ET-1 has also been implicated in the development and progression of several forms of proteinuric renal disease, and it has been suggested that these effects of ET-1 in the kidney are mediated at least in part by platelet-activating factor (PAF). Since relatively little is known about the mechanism of the proteinuria and glomerular endotheliosis observed with PE, the applicant hypothesizes that these renal manifestations of the disease are at least in part a consequence of local renal PAF production which is stimulated by elevated renal and/or circulating ET-1.
The specific aims of the proposed studies are therefore: 1) to establish and define the relationship between plasma ET-1, plasma PAF, and the development of proteinuria in sheep receiving continuous ET-1 infusion and to correlate this with a similar relationship in clinical preeclampsia in women; 2) to determine whether tissue-specific PAF synthesis can be stimulated by ET-1 in vitro, and to characterize the binding properties and cellular or tissue-specific localization of PAF receptors in ovine systemic, renal and uterine tissue; and 3) to evaluate the mechanism of PAF action within the kidney. Understanding the mechanisms of PE-related changes in renal function may provide important new avenues for therapeutic and/or preventive treatment for this prevalent disorder.
