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; 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，急性肾脏损伤史（AKI）的女性异常患有 尽管肾脏有临床证据 通过测量血清肌酐定义的概念之前的恢复。我们建立了怀孕 Sprague Dawley大鼠的Aki后模型使用缺血再灌注（IR）作为AKI的实验模型 概括了许多临床发现，包括胎儿生长限制。该提议的目的是 解决有关AKI使女性不利的机制的知识的关键差距 怀孕的结果。我们的中心假设是，在受孕之前的AKI会损害肾脏，血流动力学 通过减少一氧化氮（NO）生物利用度所需的健康怀孕所需的免疫适应性。普通的 怀孕的特征是几乎每个器官系统都深刻适应，以满足 胎儿在​​维持母亲的生理需求的同时。否是肾脏的中心调解人 健康怀孕的心血管适应，无生物利用度降低会导致不良母体 和胎儿结局，包括低出生体重。我们还表明，不需要合成酶（NOS） 女性增加T调节细胞（Treg）和未能在怀孕中扩大Treg的女性会导致肾脏和 母亲的血管功能障碍并促进胎儿生长限制。越来越多的证据表明 男性AKI后，肾脏NOS系统受到损害。 AKI对女性NO/NOS的影响尚不清楚。 AKI对怀孕生理适应的影响，包括无生物利用度的增加是 未知。我们的假设得到了强大的初步数据的支持，该数据显示了怀孕之前的AKI 1） 在受孕之前和怀孕之前降低肾脏NOS表达 怀孕怀孕和肾脏损伤，3）损害血浆体积的扩张，4）损害血管功能 怀孕和5）减少了怀孕中Treg的扩张。 AIM 1将检验AKI诱导的假设 降低没有生物利用度，这些生物利用度在妊娠中导致肾功能障碍和血管功能障碍。 我们建议AKI导致未能适当增加无介导的血液动力学适应和 无介导的等离子体体积膨胀的损失导致孕妇和胎儿结局不良。目的 2将检验以下假设：未能在怀孕中上调Treg会导致不良怀孕 阿基之后的结果。我们将确定AKI在怀孕之前如何影响Treg，以及在 怀孕改善了胎儿的生长和产妇的结局。我们建议AKI导致未能增加 不需要Treg扩展需要，这有助于进一步减少。结果将为批判性提供 所需的临床前基础，以阐明AKI后妊娠不良结局的机制，给予 改进的前和围产期护理指南的证据，并有可能确定新颖的治疗靶标的 临床试验。