Endothelial miR-17~92 protects against acute kidney injury

内皮miR-17~92预防急性肾损伤

• 批准号: 10338136
• 负责人: JACQUELINE HO
• 金额: $ 36.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-02 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10338136
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Angiogenic Factor; Animals; Blood Vessels; Blood capillaries; Blood flow; Chronic Kidney Failure; Critical Illness; Data; Endothelial Cells; Endothelium; Epithelial; Family; Hypoxia; In Vitro; Inflammatory; Injury; Injury to Kidney; Inpatients; Intervention; Investigation; Kidney; Knowledge; Laboratories; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Patients; Predisposition; Recovery; Renal function; Reperfusion Injury; Risk; Role; Sepsis; Testing; Thrombospondin 1; Time; Transcript; Transgenic Mice; Tubular formation; Work; angiogenesis; cecal ligation puncture; endothelial repair; gain of function; high risk; in vivo; injury and repair; injury recovery; loss of function; member; mortality; nephrogenesis; new therapeutic target; novel therapeutic intervention; renal ischemia; repaired; reparative capacity; response; targeted treatment; therapeutic target; therapy development; transcriptome sequencing; tumorigenesis; vascular injury

ABSTRACT Approximately 20% of all hospitalized patients and nearly 50% of critically ill inpatients are estimated to suffer from acute kidney injury (AKI), which is associated with high rates of morbidity and mortality. While the kidney may recover, the patients are at a higher risk for subsequently developing chronic kidney disease (CKD); other times, the acute injury is so severe that there is no kidney recovery. One of the hallmarks of AKI is damage to the renal microvasculature. This damage alters endothelial function, contributing to hypoxic and inflammatory injury to the renal parenchyma. Although an angiogenic response (vascular sprouting from existing vessels) is key to endothelial cell repair (and therefore AKI recovery), the renal microvasculature is thought to have a limited reparative capacity. There are currently no specific therapies for AKI, nor are there available interventions to decrease the risk of progression to CKD after AKI. Much of the current interventions are focused on the tubular epithelium. There are several knowledge gaps that need to be addressed to develop therapies targeted at the renal microvasculature, including: (1) what are the molecular mechanisms that drive endothelial repair after AKI; and (2) is it possible to modulate the capacity of the renal microvasculature for repair after AKI? Our laboratory has previously shown that the miR-17~92 cluster (including the microRNAs (miRNAs): miR-17, miR-18a, miR-19a/b, miR-20a and miR-92a) is required for normal kidney development and function. This cluster is known to regulate angiogenesis in other cellular contexts such as tumorigenesis. There is limited information regarding miRNAs in the renal vasculature in AKI, and the role of miR-17~92 in this context is unknown. Our team has generated preliminary data following renal ischemia-reperfusion injury (IRI) showing that transgenic mice lacking miR-17~92 in endothelial cells are more susceptible to renal IRI. Our central hypothesis is that miR- 17~92 promotes endothelial cell repair after injury and protects against AKI; thus making it an exciting therapeutic target. To test this hypothesis, the following specific aims are proposed: Aim 1- To define the requirement for endothelial miR-17~92 during renal injury and repair; and Aim 2- To determine whether miR-17~92 is sufficient to protect against renal injury.

摘要 据估计，约20%的住院患者和近50%的重症住院患者患有 急性肾损伤（阿基）与高发病率和死亡率相关。而肾脏 可能恢复，患者随后发生慢性肾病（CKD）的风险较高;其他 有时，急性损伤如此严重，以至于肾脏无法恢复。阿基的标志之一是对 肾脏微血管系统这种损伤改变了内皮功能，导致缺氧和炎症 肾实质损伤。虽然血管生成反应（血管从现有血管发芽）是一个重要的因素， 作为内皮细胞修复（以及因此阿基恢复）的关键，肾微血管被认为具有有限的 修复能力。目前没有针对阿基的特异性疗法，也没有可用的干预措施， 降低阿基后进展为CKD的风险。目前的大部分干预措施都集中在管状 上皮有几个知识差距，需要加以解决，以开发针对的治疗， 肾微血管系统，包括：（1）阿基后驱动内皮修复的分子机制是什么; 以及（2）是否有可能调节阿基后肾脏微血管的修复能力？ 我们的实验室先前已经表明，miR-17~92簇（包括microRNA（miRNAs）：miR-17， miR-18 a、miR-19 a/B、miR-20 a和miR-92 a）是正常肾脏发育和功能所必需的。此群集 已知在其它细胞环境如肿瘤发生中调节血管生成。信息有限 关于阿基中肾血管中的miRNA，miR-17~92在此背景下的作用尚不清楚。我们 研究小组在肾缺血再灌注损伤（IRI）后获得的初步数据显示， 内皮细胞中缺乏miR-17~92的小鼠更易发生肾IRI。我们的核心假设是miR- 17~92促进损伤后的内皮细胞修复并保护免受阿基;因此使其成为令人兴奋的治疗药物 目标为了检验这一假设，提出了以下具体目标： 目的2-确定miR-17 ~ 92是否足以在肾损伤和修复中发挥作用， 以防止肾损伤。