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: 8464084
• 负责人: Michael P Hutchens
• 金额: $ 15.12万
• 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/8464084
• 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; 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）：急性肾脏损伤（AKI）是一种不可治疗的，经常致命的疾病，在重病中很常见。与男性相比，AKI在男性中更普遍，更严重，这表明性是干预的机会。对AKI的研究最近突出了内皮细胞。雌激素是一种内皮保护剂。该建议检验了以下假设：女性受到AKI的保护，部分原因是雌激素保护肾脏内皮，从而保留整体肾功能。 AIM 1将确定心脏骤停和心肺复苏后（CA/CPR）的肾小球内皮和肾功能损伤是否是性二态性的，并由雌激素介​​导。要检验的假设是，雌激素可保护CA/CPR后两性的肾小球和管状功能。 AIM 2将重点放在分子机制上。要检验的假设是雌激素减弱了肾小球内皮功能变化，这可能会损害近端管状上皮细胞。 AIM 3将使用分子超声来评估体内模型中AIM 2的发现。要检验的假设是，由于雌激素增强了肾脏内皮完整性，因此发生了CA/CPR的女性肾脏肾脏保护。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AIM 1中的多个时间点评估肾脏结果。AIM2将在体外模型中使用小鼠肾小球内皮细胞和小鼠近端管状上皮细胞进行。哥美细胞内皮细胞与雌激素，雌激素受体拮抗剂和相关剂结合使用氧气/葡萄糖剥夺。肾小球内皮渗透性以及氧气 - 葡萄糖丧失的肾小球内皮细胞对肾小管上皮细胞的影响。 AIM 3将使用带有抗体标签的微泡对比度的分子超声来评估CA/CPR小鼠后的肾脏内皮。我们的初步数据表明，雌激素在CA/CPR后是重新保护的，这可能是通过G蛋白偶联的雌激素受体GPRR30。我们还表明，肾小球内皮渗透性在CA/CPR之后会改变，并且这些细胞在体外受到雌激素的保护。 AKI在重症患者中非常普遍，死亡率高达70％。这项研究基于这样的观察，即女性受到的影响较小。对AKI进行了重大研究，没有任何有意义的结果改变，但是这项新颖的研究提供了一种新的方法。