权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

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
项目类别：
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

项目摘要

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，有急性肾损伤（AKI）史的妇女有异常的肾损伤