Impaired Renal Reserve and Preeclampsia - Preeclampsia is one of the most common and serious medical complications of pregnancy. While there are many risk factors for the development of preeclampsia, women with underlying kidney disease are at significantly increased risk for developing preeclampsia and adverse outcomes related to preeclampsia. In women with impaired renal function, such as in women with prior history of acute kidney injury, in renal allograft recipients, in women who carry a single kidney, or in women with chronic kidney disease, an inability to increase glomerular filtration rate during pregnancy is thought to lead to excess risk of preeclampsia, though precise mechanisms are largely unknown. In recently published studies, we observed that uninephrectomized pregnant mice developed new-onset hypertension, proteinuria, and high circulating soluble fms-like tyrosine kinase 1 during the third trimester, all features reminiscent of humans with preeclampsia. In preliminary studies, we have generated a second mouse model of impaired renal reserve secondary to prior acute kidney injury that also develops preeclampsia-like syndrome during late pregnancy. To understand mechanisms, we studied plasma metabolite profiles and noted that mice with impaired renal reserve failed to upregulate L-kynurenine, a metabolite of tryptophan and that is critical for de novo nicotinamide adenine dinucleotide synthesis during pregnancy. In this proposal, we will test the hypothesis that deficiency of L-kynurenine during pregnancy in models of maternal kidney dysfunction contributes to the pathogenesis of abnormal placentation and the excess risk of preeclampsia. We will use state-of-art methods including in vivo plasma volume measurements, uterine artery blood flow measurements, preeclampsia biomarkers, transcriptomics and metabolic profiling of placental tissue and plasma to confirm a role for deficient L-kynurenine in the pathogenesis of preeclampsia in two distinct mouse models of preeclampsia due to pre-existing renal impairment. We have assembled a team of experts (physiology, metabolism, and pathology) to complement PI’s expertise in preeclampsia biology. Ultimately, our goal is to translate our findings to the bedside through improved methods of diagnosis and monitoring of preeclampsia in this high-risk population, and through design of targeted, pathophysiology-based interventions.
