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