Mechanisms of subclinical renal injury in females following AKI: implications for adverse pregnancy outcomes

最近的大规模临床研究报告，有急性肾损伤(AKI)病史的女性 尽管有肾脏的临床证据，但妊娠期间孕产妇和胎儿不良结局的发生率很高 受孕前的恢复，通过测量血清肌酐来定义。我们确定怀孕了 用脑缺血再灌注建立SD大鼠急性脑损伤模型的实验研究 总结了许多临床发现，包括胎儿生长受限。这项提议的目标是 解决关于AKI使女性容易受到不利影响的机制的知识的严重缺口 妊娠结局。我们的中心假设是，受孕前的AKI会损害肾脏的血流动力学 以及通过降低一氧化氮(NO)的生物利用度来实现健康怀孕所需的免疫适应。正常 怀孕的特点是几乎每个器官系统都有深刻的适应，以满足 胎儿在维持母亲生理需求的同时。NO是肾脏的中枢介质，而且 健康妊娠的心血管适应性和NO生物利用度的降低导致不良母体 以及胎儿结局，包括低出生体重。我们还表明，不需要合成酶(NOS)来 女性增加T调节细胞(Tregs)，怀孕期间未能扩大Tregs会导致肾脏和 母亲的血管功能障碍，并促进胎儿生长受限。越来越多的证据表明， 男性AKI后肾脏一氧化氮合酶系统受损。AKI对女性NO/NOS的影响尚不清楚。 AKI对妊娠的生理适应的影响，包括NO生物利用度的增加 未知。我们的假设得到了强有力的初步数据的支持，这些数据显示AKI在怀孕前1) 在怀孕前和怀孕期间减少肾脏一氧化氮合酶的表达，2)在怀孕前导致亚临床损伤 妊娠和妊娠期肾脏损伤，3)损害血浆容量扩张，4)损害血管功能 5)减少怀孕期间Treg的扩张。目标1将检验AKI诱导的假设 降低NO的生物利用度，在怀孕期间加剧，导致肾脏和血管功能障碍。 我们认为，AKI导致未能适当增加NO介导的血流动力学适应，并 丢失NO介导的血浆容量扩张导致妊娠期间不良的母婴结局。目标 2将检验这样一种假设，即怀孕期间未能上调Tregs会导致不良妊娠 AKI后的结果。我们将确定怀孕前AKI对Tregs的影响，以及在怀孕期间是否增加Tregs 怀孕可以改善胎儿生长和母体结局。我们认为，AKI导致未能增加 这是Treg扩展所必需的，有助于进一步减少NO。结果将提供一个关键的 需要临床前基础来阐明AKI后不良妊娠结局的机制，给予 改善产前和围产期护理指南的证据，并可能确定新的治疗目标 临床试验。

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.