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

描述（由申请人提供）：急性肾损伤（阿基）是一种无法治疗的，经常致命的疾病，这是常见的危重病。阿基在男性中比女性更常见，也更严重，这表明性行为是干预的机会。阿基的研究最近强调了内皮细胞。雌激素是一种内皮保护剂。该提案检验了女性免受阿基的部分原因是雌激素保护肾内皮，保护整体肾功能的假设。目的1：研究心脏骤停和心肺复苏（CA/CPR）后肾小球内皮和肾功能的损伤是否具有性别二型性，是否由雌激素介导。有待检验的假设是雌激素保护CA/CPR后男女的肾小球和肾小管功能。目标2将侧重于分子机制。有待检验的假设是，雌激素减弱肾小球内皮功能的变化，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。有待检验的假设是，女性肾保护CA/CPR发生，因为雌激素增强肾内皮完整性。这些假设将使用CA/CPR的体内小鼠模型进行测试，其中小鼠经历10分钟的CA，然后是CPR。在目的1中的多个时间点评估肾脏结局。目的2将在体外模型中进行，使用小鼠肾小球内皮细胞和小鼠近端肾小管上皮细胞。将肾小球内皮细胞暴露于氧/葡萄糖剥夺，与雌激素、雌激素受体拮抗剂和相关药剂组合。将评估肾小球内皮通透性和缺氧-葡萄糖剥夺的肾小球内皮细胞对肾小管上皮细胞的影响。目的3将使用分子超声结合抗体标记的微泡造影剂来评估CA/CPR后小鼠的肾内皮。我们的初步数据表明，雌激素是肾保护CA/CPR后，这可能是通过G蛋白偶联雌激素受体GPRR 30。我们还发现CA/CPR后肾小球内皮通透性改变，这些细胞在体外受到雌激素的保护。阿基在重症患者中极其常见，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。对阿基进行了大量研究，结果没有发生有意义的变化，但这项新研究提供了一种新方法。 公共卫生相关性：急性肾损伤（阿基）是一种无法治疗的常见和严重疾病，发生在危重患者中。女性可以免受阿基的影响，在动物研究中，雌激素可能具有保护作用。这项工作旨在评估雌激素保护作用的机制，希望为治疗提供可能性。

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. PUBLIC HEALTH RELEVANCE: Acute kidney injury (AKI) is an untreatable, common and severe condition which occurs in critically ill patients. Women are protected from AKI, and in animal studies, estrogen may be protective. The proposed work aims to evaluate mechanisms of estrogen's protective action with the hope of offering possibilities for treatment.