Endothelial miR-17~92 protects against acute kidney injury

内皮miR-17~92预防急性肾损伤

• 批准号: 10550222
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10550222
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Angiogenesis Inhibitors; Angiogenic Factor; Animals; Blood Vessels; Blood capillaries; Blood flow; Chronic Kidney Failure; Critical Illness; Data; Endothelial Cells; Endothelium; Epithelium; Family; Hospitalization; 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; Role; Sepsis; Testing; Thrombospondin 1; 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; progression risk; 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.

抽象的 所有住院患者中约有20％和近50％的重症患者估计受苦 急性肾脏损伤（AKI），这与高发病率和死亡率相关。而肾脏 可能会恢复，患者患慢性肾脏疾病（CKD）的风险更高；其他 时代，急性损伤是如此严重，以至于没有肾脏恢复。 AKI的标志之一是损坏 肾脏微脉管系统。这种损害改变了内皮功能，导致缺氧和炎症 肾实质受伤。尽管血管生成反应（现有血管的血管发芽）是 内皮细胞修复（因此是AKI恢复）的关键，肾脏微脉管系统被认为有限 修复能力。目前没有针对AKI的具体疗法，也没有可用的干预措施 降低AKI后进展到CKD的风险。当前的许多干预措施都集中在管状 上皮。需要解决一些知识差距，以开发针对针对的疗法 肾脏微脉管系统，包括：（1）在AKI后驱动内皮修复的分子机制是什么； （2）是否有可能调节AKI后肾脏微脉管系统进行修复的能力？ 我们的实验室以前已经表明miR-17〜92簇（包括microRNA（miRNA）：miR-17， 正常的肾脏发育和功能需要miR-18a，miR-19a/b，miR-20a和miR-92a）。这个集群 已知会在其他细胞中（例如肿瘤发生）调节血管生成。信息有限 关于AKI肾脏脉管系统中的miRNA以及Mir-17〜92在这种情况下的作用是未知的。我们的 团队在肾脏缺血再灌注损伤（IRI）后产生了初步数据，表明转基因 内皮细胞中缺乏miR-17〜92的小鼠更容易受到肾脏IRI的影响。我们的中心假设是mir- 17〜92促进受伤后的内皮细胞修复并预防AKI；因此使其成为令人兴奋的治疗 目标。为了检验该假设，提出了以下特定目的：目标1-定义要求 肾脏损伤和修复期间内皮miR-17〜92；目标2-确定mir-17〜92是否足够 防止肾脏受伤。