MicroRNA-21 in Renal Aging

描述(由申请人提供)：年龄(&gt；60岁)与急性肾损伤(AKI)后死亡率的增加有关，幸存者患有慢性肾脏疾病，每年的透析费用为100亿美元。通过包括缺血-再灌注损伤在内的动物模型，已经确定了AKI导致肾功能恢复失败和CKD的潜在机制的组成部分。细胞凋亡、炎症和细胞外基质沉积增加导致肾纤维化和肾功能衰竭。促炎症和促纤维化信号的持续激活是这一过程的重要中介。目前尚不清楚为什么老年人在AKI后恢复延迟、不完整或缺席的风险增加。在人类和啮齿动物中，核因子-kappaB通路被认为是与年龄相关的转录变化的激活因子，并被认为在组织损伤后介导GS和TIF的发展。最近发现，microRNAs在协调核因子-kappaB活化引起的细胞凋亡和促纤维化反应中发挥重要作用。MicroRNAs(MiRs)是一种小的RNA分子(19-22个核苷酸长)，通过与靶mRNAs的部分互补来协调基因表达的途径。它们是一个特别有吸引力的研究途径，因为它们作为可以调节分子通路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基因敲除小鼠的缺血再灌注损伤恢复延迟。此外，miR-21还可抑制培养的肾上皮细胞的凋亡。由于我们在衰老过程中检测到肾脏miR-21表达的增加，我们假设miR-21表达的增加起到了保护作用，通过抑制NF-kappaB途径的组成部分以及与p53和转化生长因子-β信号的串扰，阻止了损伤反应中的凋亡和促纤维化途径的激活。我们建议通过检测miR-21缺失小鼠的肾功能、组织学变化和已知的介导IR损伤的细胞机制来确定miR-21缺失是否改变了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，以确定年龄相关变化的潜在机制以及miR-21在肾脏对IR损伤的反应中的调节。我们预计，缺乏miR-21的老年小鼠将比年轻小鼠和具有完整miR-21调控机制的野生型小鼠表现出更高的缺血再灌注敏感性。MiR-21的这种保护关系的证明将开启这种微小RNA用于治疗的可能性。 公共卫生相关性：年龄增加(60岁以上)的患者如果肾脏严重受损，患上持续性肾功能减退(慢性肾脏疾病)或肾脏完全衰竭的风险更高，如果他们的肾脏严重受损，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死亡的可能性更大。由于老年人的数量继续增加，了解是什么导致不利结果的风险随着年龄的增长而上升是很重要的。我们对导致这些差异的潜在机制的了解非常有限，这也是为什么患者既没有早期发现的标志物，也没有治疗干预的原因之一。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(“microRNAs”)在肾脏损伤的发育和恢复中的作用。这些分子特别令人感兴趣，因为它们可以用作新药。其中一种microRNAs(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，这意味着肾脏持续的慢性损害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，未来的项目将探索提高miR-21水平以预防和治疗急性肾损伤的方法，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.