MicroRNA-21 in Renal Aging

描述（由申请人提供）：年龄（> 60岁）与急性肾损伤（阿基）后死亡率增加相关，幸存者留下慢性肾病和透析，每年花费100亿美元。已经使用包括缺血再灌注损伤的动物模型鉴定了导致阿基不能恢复肾功能和CKD的潜在机制的组分。细胞凋亡增加、炎症反应和细胞外基质沉积导致肾纤维化和肾功能衰竭。促炎和促纤维化信号的持续激活是该过程的重要介质。目前尚不清楚为什么老年人在阿基后延迟，不完全或不恢复的风险增加。NF-κ B通路已被鉴定为人类和啮齿动物中年龄相关转录变化的激活剂，并被认为介导组织损伤后GS和TIF的发生。最近发现micro-RNA在协调对NF-κ B活化的凋亡和促纤维化反应中起重要作用。microRNA（miRs）是小RNA分子（19-22个核苷酸长），其通过与靶mRNA的部分互补来协调基因表达途径。它们是一种特别有吸引力的研究途径，因为它们作为可调节分子途径的长效药物具有治疗潜力。我们的初步数据显示，年轻成年miR-21敲除小鼠的缺血再灌注损伤恢复延迟。此外，miR-21抑制培养的肾上皮细胞的凋亡。由于我们检测到衰老过程中肾脏中miR-21表达增加，我们假设这种增加的miR-21表达起保护作用，通过抑制NF-κ B通路的组分以及与p53和TGF-β信号传导的串扰来防止响应损伤的凋亡和促纤维化通路活化。我们建议通过检查已知介导miR-21缺失小鼠IR损伤的肾功能、组织学变化和细胞机制来确定miR-21缺失是否改变对与衰老相关的缺血再灌注损伤的反应。此外，我们将使用全基因组表达谱和系统生物学方法来比较转录网络结构的模式，来定义年龄相关变化的潜在机制及其在IR损伤的肾脏反应中由miR-21进行的调节。我们预计，缺乏miR-21的老年小鼠将表现出比年轻小鼠及其具有完整miR-21调节机制的野生型同窝小鼠更高的缺血-再灌注易感性。证明miR-21的这种保护关系将打开这种micro-RNA可以用于治疗的可能性。 公共卫生相关性：年龄增加（60岁以上）的患者有更高的风险，如果他们的肾脏受到急性损伤，则会出现持续的肾功能下降（慢性肾脏病）或完全的肾衰竭，每年给社会造成超过100亿美元的损失。此外，肾脏急性损伤的患者更有可能死亡。由于老年人的数量持续上升，因此了解是什么原因导致不利结果的风险随着年龄的增长而上升非常重要。我们对导致这些差异的潜在机制的了解非常有限，这也是为什么早期检测标记物和治疗干预措施都不能提供给患者的原因之一。为了改善这种潜在的破坏性疾病的结果，我们探索了新发现的RNA分子（“microRNA”）在肾损伤的发展和恢复中的作用。这些分子特别有趣，因为它们可以用作新药。其中一种microRNA（miR-21）似乎可以防止细胞死亡，从而保护幼鼠的肾脏。因此，我们计划研究老年小鼠，并确定miR-21的丢失是否会导致更糟糕的结果，这意味着对肾脏的持续慢性损伤或急性肾脏损伤后的死亡。如果这些研究支持miR-21的保护作用，未来的项目将探索增加miR-21水平的方法来预防和治疗急性肾损伤，从而为急性肾损伤患者开辟新的选择。

DESCRIPTION (provided by applicant): Age (>60yrs) is associated with increased mortality after acute kidney injury (AKI) with survivors being left with chronic kidney disease and on dialysis costing $10 billion per year. Components of the underlying mechanism that lead from AKI to failure to recover kidney function and CKD have been identified using animal models including ischemia-reperfusion injury. Increased apoptosis, inflammation and deposition of extracellular matrix result in renal fibrosis and renal failure. Persistent activation of pro-inflammatory and pro-fibrotic signals are important mediators of this process. It is not understood well why older individuals are at increased risk for delayed, incomplete or absent recovery after AKI. The NF-kappaB pathway has been identified as an activator of age-related transcriptional changes in human and rodents and is thought to mediate development of both GS and TIF following tissue injury. Micro-RNAs have recently been found to play an important role in coordinating the apoptotic and pro-fibrotic response to NF-kappaB activation. microRNAs (miRs), are small RNA molecules (19-22 nucleotides long) that coordinate pathways of gene expression via partial complementary to target mRNAs. They are a particularly attractive avenue for investigation because of their therapeutic potential as long-lasting drugs that can modulate molecular pathways. Our preliminary data show delayed recovery from ischemia-reperfusion injury in young adult miR-21 knockout mice. In addition, miR-21 inhibits apoptosis in cultured renal epithelial cells. Because we detected increasing miR-21 expression in the kidney during aging, we hypothesize that this increased miR-21 expression plays a protective role that prevents activation of the apoptotic and pro-fibrotic pathway activation in response to injury through inhibiting components of the NF-kappaB pathway and crosstalk with p53 and TGF-beta signaling. We propose to determine whether loss of miR-21 alters the response to ischemia-reperfusion injury associated with aging by examining renal function, histologic changes and cellular mechanisms known to mediate IR injury in miR-21 null mice. Furthermore, we will define the underlying mechanism of age-associated changes and its regulation by miR-21 in the renal response to IR injury using genome-wide expression profiling and a systems biology approach to compare patterns of transcriptional network structures. We expect that old mice lacking miR-21 will exhibit increased susceptibility to ischemia-reperfusion than young mice and their wildtype litter-mates with an intact miR-21 regulatory machinery. Demonstration of this protective relationship for miR-21 will open up the possibility that this micro-RNA could be used therapeutically. PUBLIC HEALTH RELEVANCE: Patients of increased age (above 60 years) have a higher risk to have persistent decreased kidney function (Chronic Kidney Disease) or complete failure of the kidneys if their kidneys are damaged acutely costing the society over $10 billion per year. In addition, patients with acute injury of the kidneys are more likely to die. Because the number of older adults continues to rise, it is important to understand what causes the risk of an unfavorable outcome to rise with age. Our knowledge about the underlying mechanisms that are responsible for these differences are very limited and this is one reason why neither markers for early detection nor therapeutic interventions are available to patients. To improve the outcome of this potentially devastating disease, we have explored the role of newly discovered RNA molecules ("microRNAs") in development and recovery from kidney injury. These molecules are in particular interesting because they could be used as new drugs. One of these microRNAs (miR-21) appears to prevent cell death and thereby protect the kidney in young mice. Therefore, we plan to study older mice and determine whether loss of miR-21 leads to worse outcome meaning persistent chronic damage to the kidneys or death after an acute injury to the kidneys. If these studies support a protective role of miR-21, future project will explore ways to increase miR-21 levels to prevent and treat acute kidney injury and thereby open new options for patient with acute kidney injury.