Age-Dependent Nephrotoxicity Involved Loss of the N-cadherin/a-catenin Complex

年龄依赖性肾毒性涉及 N-钙粘蛋白/α-连环蛋白复合物的丢失

基本信息

批准号：
8181481
负责人：
ALAN R PARRISH
金额：
$ 21.4万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8181481
关键词：
Actins Acute Acute Kidney Failure Acute Renal Failure with Renal Papillary Necrosis Address Adhesions Affect Age Aging Cadherins Cell Aging Cells Chronic Kidney Failure Complex Complication Cytoskeleton Data Elderly Environmental Exposure Epithelial Epithelial Cells Exposure to Harvest Hospitals In Vitro Incidence Injury Injury to Kidney Kidney Kidney Diseases Kidney Failure Knowledge Laboratories Lead Link Mediating Mercuric chloride Mercury Modeling Molecular Morbidity - disease rate N-Cadherin Nephrotoxic Outcome Pathway interactions Patients Population Predisposition Public Health Rattus Recovery Risk Factors Role Secondary to Series Severities Slice Small Interfering RNA Structure Testing Toxic effect Tubular formation age related aged base cell age cell motility design in vitro Model in vivo injury and repair laser capture microdissection mortality nephrotoxicity novel overexpression public health relevance repaired research study response response to injury

项目摘要

DESCRIPTION (provided by applicant): The percentage of the U.S. population over 65 is rapidly increasing, as is the incidence of chronic kidney disease (CKD). There is an increasing recognition that age and CKD are risk factors for acute kidney injury (AKI) and that AKI most often develops as an acute-on-chronic injury. We have characterized an age- dependent model of CKD in our laboratory, which recapitulates the increased incidence and severity of acute kidney injury in the elderly. Our data demonstrate that aging is associated with loss of the N-cadherin/?-catenin complex; the N-cadherin/?-catenin complex is a target of nephrotoxic injury; and aging is associated with an increased susceptibility of tubular epithelial cells to acute injury. Based on these data, we hypothesize that the age-dependent loss of the N-cadherin/?-catenin complex increases susceptibility to nephrotoxicity. Four Specific Aims have been designed to examine this hypothesis. In Aim 1, the link between age-related loss of N-cadherin and susceptibility to mercuric chloride, a relevant environmental nephrotoxicant, will be examined in vivo. These studies will focus on the hypothesis that that both increased injury and diminished repair from nephrotoxic injury distinguish the aged kidneys. In Aim 2, the direct relationship between N-cadherin loss and susceptibility to mercuric chloride will be examined in vitro using a number of molecular approaches, including overexpression and knockdown strategies. Aim 3 will test the hypothesis loss of ?-catenin leads to disorganization of the actin cytoskeleton via increased Arp2/3 activity and decreased formin-1 mediated nucleation of linear actin cables, predisposing the aged kidney to nephrotoxic insult. Finally, in Aim 4, we will develop an inducible, proximal tubular epithelial-specific ?-catenin knockout mouse to our hypothesis in vivo. These studies will be the first data to link expression of the cadherin/catenin complex with response to injury; the link between loss of N-cadherin/?-catenin and injury has tremendous implications in our understanding of mechanisms of toxicity. In addition, these studies address a novel pathway underlying the increased susceptibility of the aging kidney to injury. Taken together, these studies represent a significant advance in attempts to manage the increasing burden of renal disease in the expanding geriatric population. PUBLIC HEALTH RELEVANCE: Aging is associated with alterations in renal structure and function, which may predispose geriatric patients to acute kidney injury following exposure to nephrotoxicants. In these studies, we will examine changes that lead to the increased susceptibility of the aging kidney to injury.

描述（由申请人提供）：与慢性肾脏疾病（CKD）的发生率一样，美国人口的百分比正在迅速增加。人们越来越认识到年龄和CKD是急性肾脏损伤（AKI）的危险因素，并且AKI最常作为急性在智力损伤中发展。我们表征了我们实验室中CKD的年龄依赖模型，该模型概括了老年人急性肾脏损伤的发病率和严重程度。我们的数据表明，衰老与N-钙粘蛋白/？ - catenin复合物的丧失有关； N-钙粘蛋白/？ - catenin复合物是肾毒性损伤的靶标。衰老与肾小管上皮细胞对急性损伤的敏感性增加有关。基于这些数据，我们假设N-钙粘蛋白的年龄依赖性损失/？ - catenin络合物增加了对肾毒性的敏感性。已经设计了四个特定目标来检验这一假设。在AIM 1中，将在体内检查与年龄相关的N-钙粘蛋白损失与氯化汞含量（一种相关的环境肾毒性）之间的联系。这些研究将集中于以下假设：肾毒性损伤增加了损伤和减少修复会区分老年肾脏。在AIM 2中，将在体外使用多种分子方法（包括过表达和敲低策略）在体外检查N-钙粘蛋白损失与易感性之间的直接关系。 AIM 3将通过增加的ARP2/3活性来测试？ - 蛋白酶的假设丧失会导致肌动蛋白细胞骨架的混乱，并降低了线性肌动蛋白电缆的formin-1介导的成核，使老年肾脏对肾毒性的损害产生了易感性。最后，在AIM 4中，我们将开发一个可诱导的，近端的肾小管上皮特异性？-Catenin敲除小鼠，以在体内假设。这些研究将是将钙粘蛋白/catenin复合物与损伤反应联系起来的第一个数据。 N-钙粘蛋白/？ - catenin和损伤之间的联系在我们对毒性机制的理解中具有巨大的影响。此外，这些研究介绍了衰老肾脏受伤的敏感性增加的基础的新途径。综上所述，这些研究代表了试图管理不断扩大的老年人群的肾脏疾病负担的重大进步。公共卫生相关性：衰老与肾脏结构和功能的改变有关，这可能使老年患者易于接触肾毒性后急性肾脏损伤。在这些研究中，我们将研究变化，从而导致肾脏对损伤的敏感性增加。