Recent large-scale clinical studies report that women with a history of acute kidney injury (AKI) have abnormally
high rates of adverse maternal and fetal outcomes during pregnancy, despite clinical evidence of renal
recovery prior to conception as defined by measurement of serum creatinine. We established a pregnancy
post-AKI model in Sprague Dawley rats using ischemia reperfusion (IR) as an experimental model of AKI which
recapitulates many of the clinical findings, including fetal growth restriction. The goal of this proposal is to
address a critical gap in knowledge regarding the mechanisms by which AKI predisposes females to adverse
outcomes in pregnancy. Our central hypothesis is that AKI prior to conception impairs the renal, hemodynamic
and immune adaptations required for a healthy pregnancy by decreasing nitric oxide (NO) bioavailability. Normal
pregnancy is characterized by profound adaptations in almost every organ system to meet the demands of the
fetus while maintaining the physiological needs of the mother. NO is a central mediator of the renal and
cardiovascular adaptations in healthy pregnancy, and decreases in NO bioavailability lead to adverse maternal
and fetal outcomes, including low birth weight. We have also shown that NO synthase (NOS) is required for
females to increase T regulatory cells (Tregs), and failure to expand Tregs in pregnancy induces renal and
vascular dysfunction in the mother and promotes fetal growth restriction. There is growing evidence that the
renal NOS system is impaired following AKI in males. The impact of AKI on NO/NOS in females is unknown.
The impact of AKI on physiological adaptations to pregnancy, including increases in NO bioavailability are
unknown. Our hypothesis is supported by strong preliminary data showing AKI prior to pregnancy 1)
decreases renal NOS expression prior to conception and in pregnancy, 2) results in subclinical injury prior to
pregnancy and renal injury in pregnancy, 3) impairs plasma volume expansion, 4) impairs vascular function in
pregnancy, and 5) decreases Treg expansion in pregnancy. Aim 1 will test the hypothesis that AKI induces
reductions in NO bioavailability that are exacerbated in pregnancy resulting in renal and vascular dysfunction.
We propose that AKI results in the failure to appropriately increase NO-mediated hemodynamic adaptations and
loss of NO-mediated plasma volume expansion leading to poor maternal and fetal outcomes in pregnancy. Aim
2 will test the hypothesis that failure to upregulate Tregs in pregnancy contributes to adverse pregnancy
outcomes post-AKI. We will determine how AKI prior to pregnancy impacts Tregs and if increasing Tregs during
pregnancy improves fetal growth and maternal outcomes. We propose that AKI results in the failure to increase
NO which is required for Treg expansion, contributing to further decreases in NO. Results will provide a critically
needed pre-clinical foundation to elucidate the mechanisms underlying poor pregnancy outcomes after AKI, give
evidence for improved pre- and perinatal care guidelines, and potentially identify novel therapeutic targets for
clinical trials.
