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:
  • 金额:
    $ 46.57万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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Jennifer C Sullivan其他文献

Jennifer C Sullivan的其他文献

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{{ truncateString('Jennifer C Sullivan', 18)}}的其他基金

Improving awareness of women with hypertension: ROAR (Rural, Obese, At Risk) - Leadership Administrative Core (LAC)
提高女性高血压患者的意识:ROAR(农村、肥胖、危险)- 领导行政核心 (LAC)
  • 批准号:
    10714534
  • 财政年份:
    2023
  • 资助金额:
    $ 46.57万
  • 项目类别:
Improving awareness of women with hypertension: ROAR (Rural, Obese, At Risk)
提高女性高血压患者的意识:ROAR(农村、肥胖、危险)
  • 批准号:
    10714530
  • 财政年份:
    2023
  • 资助金额:
    $ 46.57万
  • 项目类别:
Mechanisms Driving Enhanced Susceptibility of Females versus Males to High-Fat Diet-Induced Increases in High Blood Pressure
女性与男性相比,对高脂肪饮食引起的高血压的易感性增强的机制
  • 批准号:
    10714531
  • 财政年份:
    2023
  • 资助金额:
    $ 46.57万
  • 项目类别:
Sex Differences in Hypertension: Contribution of DAMPs
高血压的性别差异:DAMP 的贡献
  • 批准号:
    10094231
  • 财政年份:
    2017
  • 资助金额:
    $ 46.57万
  • 项目类别:
Bioinflammation Core
生物炎症核心
  • 批准号:
    10094228
  • 财政年份:
    2017
  • 资助金额:
    $ 46.57万
  • 项目类别:
Mechanisms of T Cell-Mediated Hypertension In Females and Males
女性和男性 T 细胞介导的高血压机制
  • 批准号:
    9198049
  • 财政年份:
    2016
  • 资助金额:
    $ 46.57万
  • 项目类别:
Mechanisms of T cell-mediated hypertension in females and males
女性和男性 T 细胞介导的高血压机制
  • 批准号:
    9028818
  • 财政年份:
    2016
  • 资助金额:
    $ 46.57万
  • 项目类别:
Animal Core
动物核心
  • 批准号:
    8002615
  • 财政年份:
    2010
  • 资助金额:
    $ 46.57万
  • 项目类别:
Sexual dimorphisms of renin-angiotensin system in hypertension and renal injury
高血压和肾损伤中肾素-血管紧张素系统的性别二态性
  • 批准号:
    8307938
  • 财政年份:
    2009
  • 资助金额:
    $ 46.57万
  • 项目类别:
Role of the renin-angiotensin system in sexual dimorphisms in the development of
肾素-血管紧张素系统在性二态性发育中的作用
  • 批准号:
    7851391
  • 财政年份:
    2009
  • 资助金额:
    $ 46.57万
  • 项目类别:

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