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

AKI 后女性亚临床肾损伤的机制：对不良妊娠结局的影响

• 批准号: 10568101
• 负责人: Jennifer C Sullivan
• 金额: $ 46.57万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-08 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568101
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Biological Availability; Blood Plasma Volume; Blood Vessels; Cardiovascular system; Caring; Chronic Kidney Failure; Clinical; Clinical Data; Clinical Research; Clinical Trials; Conceptions; Coupled; Creatinine; Data; Event; Exhibits; Experimental Models; Failure; Female; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetus; Foundations; Glomerular Filtration Rate; Goals; Guidelines; Health; Hospitalization; Human; Immune; Impairment; Injury; Injury to Kidney; Ischemia; Kidney; Knowledge; Lead; Low Birth Weight Infant; Maternal Health; Measurement; Mediating; Mediator; Modeling; Mothers; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Outcome; Patients; Perfusion; Perinatal; Perinatal Care; Peripheral Resistance; Physiological; Physiological Adaptation; Plasma; Pregnancy; Pregnancy Outcome; Prevention; Production; Publishing; Rattus; Recording of previous events; Recovery; Regulatory T-Lymphocyte; Reperfusion Therapy; Reporting; Research; Risk; Risk Factors; Role; Serum; Sodium; Sprague-Dawley Rats; System; Testing; United States; Vascular Diseases; Woman; absorption; adverse outcome; adverse pregnancy outcome; body system; clinical care; experience; fetal; healthy pregnancy; hemodynamics; improved; insight; kidney dysfunction; male; maternal outcome; mortality; new therapeutic target; novel; post pregnancy; pre-clinical; prenatal; prevent; research study; screening; sex; urinary

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.

最近的大规模临床研究报告说，有急性肾损伤（阿基）病史的妇女， 尽管有肾脏疾病的临床证据，但妊娠期间不良孕产妇和胎儿结局的发生率较高 通过测量血清肌酐定义的受孕前恢复。我们证实了她怀孕了 使用缺血再灌注（IR）作为阿基的实验模型， 概括了许多临床发现，包括胎儿生长受限。本提案的目的是 解决关于阿基使女性易患不良反应的机制的知识方面的关键空白 妊娠的结果。我们的中心假设是，阿基在怀孕前损害肾脏血流动力学， 以及通过降低一氧化氮（NO）的生物利用度来实现健康妊娠所需的免疫适应。正常 怀孕的特点是几乎每个器官系统都有深刻的适应性，以满足怀孕的需要。 胎儿，同时保持母亲的生理需求。NO是肾脏的中心介质， 健康妊娠中的心血管适应，以及NO生物利用度的降低导致不利的母体 和胎儿结局，包括低出生体重。我们还表明，一氧化氮合酶（NOS）是必需的， 女性增加调节性T细胞（T细胞），妊娠期T细胞扩增失败诱导肾和 血管功能障碍的母亲，并促进胎儿生长限制。越来越多的证据表明， 男性阿基后肾NOS系统受损。阿基对女性NO/NOS的影响尚不清楚。 阿基对妊娠生理适应的影响，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，这些数据显示怀孕前发生阿基1） 在受孕前和妊娠期降低肾NOS表达，2）在受孕前导致亚临床损伤， 妊娠和妊娠中的肾损伤，3）损害血浆容量扩张，4）损害妊娠中的血管功能， 5）减少妊娠期Treg扩增。目的1将检验阿基诱导 NO生物利用度的降低在妊娠中加剧，导致肾和血管功能障碍。 我们认为阿基导致不能适当增加NO介导的血流动力学适应， NO介导的血浆容量扩张的丧失导致妊娠期母体和胎儿结局不良。目的 2将检验在妊娠中未能上调TdR有助于不良妊娠的假设 AKI后的结果。我们将确定妊娠前阿基如何影响TBI，以及妊娠期间TBI是否增加。 怀孕改善胎儿生长和母亲的结果。我们认为，阿基导致未能增加 NO是Treg扩增所需的，有助于NO的进一步降低。 需要临床前基础来阐明阿基后不良妊娠结局的机制， 改善产前和围产期护理指南的证据，并可能确定新的治疗靶点， 临床试验