Sex Difference in Renal Injury After Cardiac Arrest:Mechanisms of Estrogen Action

心脏骤停后肾损伤的性别差异：雌激素作用机制

• 批准号: 8300044
• 负责人: Michael P Hutchens
• 金额: $ 15.19万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300044
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Affect; Animals; Antibodies; Attenuated; Cardiopulmonary Resuscitation; Cell Death; Cell-Cell Adhesion; Cells; Coagulation Process; Coupled; Critical Illness; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Diabetic Nephropathy; Discipline; Disease; Dose; Endothelial Cells; Endothelium; Environment; Epithelial; Epithelial Cells; Estradiol; Estrogen Receptors; Estrogen Therapy; Estrogens; Female; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Glucose; Heart Arrest; Hypoxia; In Vitro; Inflammation; Injury; Intervention; Investigation; Ischemia; Kidney; Ligands; Mediating; Mediator of activation protein; Mentorship; Methodology; Microbubbles; Modeling; Molecular; Mus; Outcome; Oxygen; Pathway interactions; Patients; Permeability; Positioning Attribute; Process; Proteins; Proteinuria; Regimen; Regulation; Renal function; Reperfusion Therapy; Research; Risk; Route; Severities; Sex Characteristics; Signal Transduction; Specificity; Surface; Testing; Therapeutic; Time; Tubular formation; Ultrasonography; Vascular Endothelium; Woman; Work; base; clinically relevant; deprivation; glomerular endothelium; in vitro Model; in vivo; in vivo Model; interstitial; male; men; mortality; mouse model; multidisciplinary; novel; novel strategies; protective effect; renal ischemia; response; sex; sexual dimorphism

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is an untreatable, frequently lethal malady which is common in the critically ill. AKI is more common and more severe in men than women, suggesting sex represents an opportunity for intervention. Investigation of AKI has recently highlighted endothelial cells. Estrogen is an endothelial protectant. This proposal tests the hypothesis that females are protected from AKI in part because estrogen protects renal endothelium, preserving overall renal function. Aim 1 will determine whether glomerular endothelial and renal functional injury after cardiac arrest and cardiopulmonary resuscitation (CA/CPR) is sexually dimorphic and mediated by estrogen. The hypothesis to be tested is that estrogen protects glomerular and tubular function in both sexes after CA/CPR. Aim 2 will focus on molecular mechanisms. The hypothesis to be tested is that estrogen attenuates glomerular endothelial functional changes which may damage proximal tubular epithelial cells. Aim 3 will use molecular ultrasound to evaluate the findings of aim 2 in an in vivo model. The hypothesis to be tested is that female renoprotection from CA/CPR occurs because estrogen augments renal endothelial integrity. These hypotheses will be tested using an in vivo mouse model of CA/CPR in which mice undergo 10 minutes of CA followed by CPR. Renal outcomes are assessed at multiple time points in aim 1. Aim 2 will be conducted in an in vitro model, using mouse glomerular endothelial cells and mouse proximal tubular epithelial cells. Gomerular endothelial cells are exposed to oxygen/glucose deprivation, in combination with estrogen, estrogen receptor antagonists, and related agents. Glomerular endothelial permeability and the effect of oxygen-glucose deprived glomerular endothelial cells on tubular epithelial cells will be assessed. Aim 3 will use molecular ultrasound with antibody-tagged microbubble contrast to assess renal endothelium in post-CA/CPR mice. Our preliminary data indicate that estrogen is renoprotective after CA/CPR, and that this may be through the G protein-coupled estrogen receptor GPRR30. We have also shown that glomerular endothelial permeability is altered after CA/CPR, and that these cells are protected by estrogen in vitro. AKI is extremely common in critically ill patients and has up to 70% mortality. This research is based on the observation that females are less affected. Significant research has been performed on AKI without meaningful change in outcome, but this novel research offers a new approach.

描述（由申请人提供）： 急性肾损伤 (AKI) 是一种无法治愈、常常致命的疾病，在危重病人中很常见。 AKI 在男性中比女性更常见、更严重，这表明性行为是干预的一个机会。最近对 AKI 的研究重点关注内皮细胞。雌激素是一种内皮保护剂。该提案检验了这样的假设：女性之所以能够免受 AKI 的影响，部分原因是雌激素可以保护肾内皮，从而保持整体肾功能。目标 1 将确定心脏骤停和心肺复苏 (CA/CPR) 后肾小球内皮和肾功能损伤是否具有性别二态性并由雌激素介​​导。待检验的假设是，CA/CPR 后雌激素可保护两性的肾小球和肾小管功能。目标 2 将重点关注分子机制。要测试的假设是雌激素减弱肾小球内皮功能变化，这可能会损害近端肾小管上皮细胞。目标 3 将使用分子超声在体内模型中评估目标 2 的发现。待检验的假设是，女性对 CA/CPR 的肾脏保护作用是由于雌激素增强肾内皮完整性而发生的。这些假设将使用 CA/CPR 的体内小鼠模型进行测试，其中小鼠接受 10 分钟的 CA，然后进行 CPR。在目标 1 的多个时间点评估肾脏结果。目标 2 将使用小鼠肾小球内皮细胞和小鼠近端肾小管上皮细胞在体外模型中进行。将戈小球内皮细胞暴露于缺氧/葡萄糖条件下，并结合雌激素、雌激素受体拮抗剂和相关药物。将评估肾小球内皮通透性以及氧-葡萄糖剥夺的肾小球内皮细胞对肾小管上皮细胞的影响。目标 3 将使用分子超声和抗体标记的微泡对比来评估 CA/CPR 小鼠的肾内皮。我们的初步数据表明，雌激素在 CA/CPR 后具有肾脏保护作用，这可能是通过 G 蛋白偶联雌激素受体 GPRR30 实现的。我们还表明，CA/CPR 后肾小球内皮细胞通透性发生改变，并且这些细胞在体外受到雌激素的保护。 AKI 在危重患者中极为常见，死亡率高达 70%。这项研究是基于女性受影响较小的观察结果。对 AKI 进行的大量研究并未对结果产生有意义的改变，但这项新颖的研究提供了一种新方法。