Endothelial miR-17~92 protects against acute kidney injury

摘要 据估计，大约20%的住院患者和近50%的危重住院患者 急性肾损伤(AKI)，与高发病率和死亡率有关。而肾则 可能康复，患者随后发展为慢性肾病(CKD)的风险更高；其他 有时，急性损伤如此严重，以至于肾脏无法恢复。AKI的标志之一是对 肾脏微血管系统。这种损伤会改变内皮功能，导致缺氧和炎症。 肾实质损伤。尽管血管生成反应(从现有血管萌发的血管)是 作为内皮细胞修复(并因此恢复AKI)的关键，肾微血管系统被认为具有有限的 补偿能力。目前还没有针对AKI的特定疗法，也没有可用的干预措施来 降低AKI后进展为CKD的风险。目前的许多干预措施都集中在肾小管上。 上皮组织。有几个知识差距需要解决，以开发针对 肾微血管系统，包括：(1)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后肾微血管的修复能力？ 我们实验室先前已经证明miR-17~92簇(包括microRNAs(MiRNAs)：miR-17， MIR-18a、miR-19a/b、miR-20a和miR-92a)是正常肾脏发育和功能所必需的。此群集 已知在其他细胞环境中调节血管生成，如肿瘤发生。有限的信息 关于miRNAs在AKI肾血管系统中的作用，miR-17~92在这方面的作用尚不清楚。我们的 研究小组在肾缺血再灌注损伤(IRI)后产生的初步数据显示，转基因 内皮细胞miR-17~92缺失的小鼠更易发生肾脏IRI。我们的中心假设是miR- 17~92促进损伤后内皮细胞修复并防止AKI；从而使其成为令人兴奋的治疗方法 目标。为了检验这一假设，提出了以下具体目标：目标1-定义以下要求 肾损伤和修复过程中的内皮miR-17~92；以及目标2-确定miR-17~92是否足够 以保护肾脏免受损伤。

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.