Sidekick-1 Upregulation in Podocytes Induces FSGS by Disrupting MAGI-1 Function

足细胞中 Sidekick-1 上调通过破坏 MAGI-1 功能诱导 FSGS

• 批准号: 8115089
• 负责人: Lewis Kaufman
• 金额: $ 33.23万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115089
• 关键词: Actinin; Adhesions; Adult; Affect; Architecture; BAIAP1 gene; Binding; Biopsy Specimen; Cell Adhesion Molecules; Cells; Data; Defect; Development; Disease; Electrons; End stage renal failure; Focal Segmental Glomerulosclerosis; Functional disorder; Goals; HIV; Health; Human; Injury; Kidney; Knockout Mice; Label; Lead; Mediator of activation protein; Microscopic; Modeling; Mus; Nephrosis; Nephrotic Syndrome; Pathogenesis; Pathway interactions; Phenotype; Play; Predisposition; Process; Proteins; Proteinuria; Renal glomerular disease; Reporting; Rodent Model; Role; Staging; Structure; Testing; Time; Transgenic Mice; Transgenic Organisms; United States; Up-Regulation; glomerulosclerosis; mouse model; nephrin; new therapeutic target; novel; novel therapeutics; overexpression; podocyte; slit diaphragm; synaptopodin; therapeutic target

DESCRIPTION (provided by applicant): Focal and segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome and end-stage renal disease worldwide. Although the mechanisms underlying this important disease are poorly understood, it is clear that the glomerular podocyte plays a central role in disease pathogenesis. In the current proposal, we demonstrate that the homophilic adhesion molecule sidekick-1 (sdk-1) is dramatically upregulated in podocytes in FSGS both in rodent models and in human kidney biopsy samples. We show that sdk-1 strongly interacts with the slit diaphragm linker protein MAGI-1, which is already known to interact with several critical podocyte proteins including synaptopodin, a-actinin-4, nephrin, JAM4, and ¿-catenin. Furthermore, transgenic mice with podocyte-specific overexpression of sdk-1 develop gradual proteinuria, nephrosis, and FSGS. Similarly, MAGI-1 deficient mice also develop gradually progressive proteinuria and FSGS. The similarities between the phenotypes of these two novel mouse models and the fact that the two involved proteins directly interact suggest that similar pathogenic factors may be involved in both models. We hypothesize that the overexpression of sdk-1 in podocytes in FSGS disrupts the ability of MAGI-1 to stabilize podocyte architecture and that over time this leads to the development of glomerular sclerosis. To confirm and identify the involved mechanisms, we propose three specific aims: 1) To determine how the overexpression of sdk-1 affects the binding of MAGI-1 to other critical podocyte proteins. 2) To characterize the renal phenotype of MAGI-1 null mice and to compare it to the phenotype of the podocyte-specific sdk-1 overexpression model. 3) To test the susceptibility of sdk-1 knockout mice to podocyte injury and to the development of FSGS. In this way, we will demonstrate that sdk-1 upregulation is an important factor contributing to the pathogenesis of FSGS and could represent a novel therapeutic target. PUBLIC HEALTH RELEVANCE: Focal and segmental glomerulosclerosis is the leading cause of idiopathic nephrotic syndrome in the United States and the most common cause of end stage renal disease caused by primary glomerular disease worldwide. In this project, we identify a novel mechanism that contributes greatly to the pathogenesis of this important disease and may lead to the identification of novel potential therapeutic targets.

描述（由申请人提供）：局灶性节段性肾小球硬化症（FSGS）是全世界肾病综合征和终末期肾病的主要原因，尽管人们对这种重要疾病的机制知之甚少，但很明显肾小球足细胞起着核心作用。在当前的提议中，我们证明同源粘附分子 sidekick-1 (sdk-1) 在足细胞中显着上调。在啮齿动物模型和人类肾活检样本的 FSGS 中，我们表明 sdk-1 与缝隙隔膜连接蛋白 MAGI-1 强烈相互作用，已知 MAGI-1 与几种关键的足细胞蛋白相互作用，包括突触蛋白、a-actinin-4。 、去氧肾上腺素、JAM4 和 ¿此外，足细胞特异性过度表达 sdk-1 的转基因小鼠会逐渐出现蛋白尿、肾病和 FSGS，MAGI-1 缺陷小鼠也会逐渐出现进行性蛋白尿和 FSGS。这两种新型小鼠的表型之间存在相似之处。模型以及两种相关蛋白直接相互作用的事实表明，两种模型中可能涉及相似的致病因素，我们发现足细胞中 sdk-1 的过度表达。 FSGS 破坏了 MAGI-1 稳定足细胞结构的能力，随着时间的推移，这会导致肾小球硬化的发展。为了确认和确定所涉及的机制，我们提出了三个具体目标：1) 确定 sdk-1 的过度表达是如何发生的。影响 MAGI-1 与其他关键足细胞蛋白的结合 2) 表征 MAGI-1 缺失小鼠的肾脏表型，并将其与足细胞特异性 sdk-1 的表型进行比较。 3) 测试sdk-1敲除小鼠对足细胞损伤和FSGS发展的敏感性通过这种方式，我们将证明sdk-1上调是促进FSGS发病的重要因素。公共卫生相关性：局灶性和节段性肾小球硬化症是美国特发性肾病综合征的主要原因。以及全球原发性肾小球疾病引起的终末期肾病的最常见原因。在该项目中，我们确定了一种新机制，该机制对这种重要疾病的发病机制有很大贡献，并可能导致新的潜在治疗靶点的确定。