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（AKI）是一种无法治愈的、经常致命的疾病，常见于危重病人。AKI在男性中比女性更常见，更严重，这表明性别代表着干预的机会。最近AKI的研究重点是内皮细胞。雌激素是一种内皮保护剂。这一建议验证了女性免受AKI的部分原因是雌激素保护肾内皮，维持整体肾功能的假设。目的1将确定心脏骤停和心肺复苏（CA/CPR）后的肾小球内皮和肾功能损伤是否性别二态并由雌激素介导。待验证的假设是雌激素在CA/CPR后保护两性肾小球和小管功能。目标2将侧重于分子机制。要验证的假设是雌激素减轻肾小球内皮功能的改变，这可能损害近端小管上皮细胞。Aim 3将使用分子超声来评估Aim 2在体内模型中的发现。需要验证的假设是CA/CPR的女性肾保护发生是因为雌激素增强了肾内皮的完整性。这些假设将通过CA/CPR的体内小鼠模型进行验证，在该模型中，小鼠进行10分钟的CA，然后进行CPR。目的1在多个时间点评估肾脏预后。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小管上皮细胞。胶质内皮细胞暴露于缺氧/葡萄糖剥夺，与雌激素、雌激素受体拮抗剂和相关药物联合使用。我们将评估肾小球内皮细胞的通透性以及缺氧葡萄糖对小管上皮细胞的影响。目的3将使用分子超声和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，CA/CPR后雌激素具有肾保护作用，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后肾小球内皮通透性发生改变，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%。这项研究是基于对女性受影响较小的观察。对AKI进行了大量的研究，但没有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的方法。

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.