Renal Protective Effects of Circulating Angiopoietin-like-4

循环血管生成素样 4 的肾脏保护作用

基本信息

批准号：
8671497
负责人：
Sumant Singh Chugh
金额：
$ 31.97万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-10 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8671497
关键词：
Adipose tissue Affect Albumins Angiopoietins Beta-N-Acetylglucosaminidase Binding Binding Proteins Buffaloes Characteristics Chronic Kidney Failure Development Diabetic Nephropathy Disease End stage renal failure Endothelial Cells Endothelium Family Fatty Acids Feedback Focal Segmental Glomerulosclerosis Gene Expression Gene Targeting Glomerular Capillary Glycoproteins Goals Heart High Density Lipoproteins Human Hydrogen Peroxide Hydrolysis Hyperlipidemia Hypertriglyceridemia Hypoalbuminemia Integrins Kidney Knockout Mice Laboratories Link Liver Medicine Modeling Modification Molecular Mus Mutation Nature Nephrotic Syndrome Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Organ Pathogenesis Pathway interactions Patients Peripheral Peroxisome Proliferator-Activated Receptors Plasma Plasma Albumin Process Proteins Proteinuria Rattus Recombinants Relative (related person)Renal glomerular disease Renin-Angiotensin System Role Severities Site Skeletal Muscle Testing Therapeutic Therapeutic Agents Transgenic Organisms Triglycerides United States Up-Regulation base diabetic glomerular endothelium glomerulosclerosis human angiopoietin-like 4 protein lipoprotein lipase mutant novel overexpression podocyte protective effect public health relevance skeletal social standard of care uptake urinary

项目摘要

DESCRIPTION (provided by applicant): Reducing proteinuria slows the progression of chronic kidney disease. The current standard of care is to block of the renin - angiotensin system at various levels to reduce proteinuria. However, reduction of proteinuria is often incomplete, since other pathways involved in the pathogenesis or modification of proteinuria are not affected by this therapy. The long term goal of the PI's lab is to develop novel mechanism - based therapeutic agents that will reduce proteinuria and reduce the progression of chronic kidney disease due to glomerular disorders. Reducing the progression of chronic kidney disease to end stage kidney disease will have a major positive social and financial impact in the United States and worldwide. The PI's laboratory has discovered a major role of the circulating glycoprotein Angiopoietin-like-4 (Angptl4) in human and experimental nephrotic syndrome. Studies conducted by his team show that circulating Angptl4 is the first molecular link between proteinuria, hypoalbuminemia and hypertriglyceridemia, three major components of nephrotic syndrome. In glomerular disease, increased Angptl4 secretion from skeletal muscle, heart, liver and adipose tissue occurs when proteinuria becomes moderate to severe (in the human context, when it reaches nephrotic range). Circulating Angptl4 reduces proteinuria by binding to glomerular endothelial ?v?5 integrin, while also inducing hypertriglyceridemia by inhibiting the activity of endothelium bound lipoprotein lipase. Further, it appears that this multi-organ upregulation of Angptl4 expression results from an increase in the plasma free fatty acid / albumin ratio. The PI has developed four new mutant forms of human Angptl4 protein that reduce proteinuria in rat models of focal and segmental glomerulosclerosis (FSGS) and diabetic nephropathy without significantly affecting plasma triglyceride levels. In Specific Aim 1, the relationship between elevated plasma free fatty acid / albumin ratio with increased peripheral organ Angptl4 expression in nephrotic syndrome will be investigated further using organ specific PPAR knockout mice. In Specific Aim 2, we will test whether administration of mutant human Angptl4 twice every month, or transgenic expression of rat Angptl4 from adipose tissue can reduce glomerulosclerosis and progression of chronic kidney disease in rats models of FSGS or diabetic nephropathy. In Specific Aim 3, mechanisms by which the interaction of circulating Angptl4 with glomerular endothelial ?v?5 integrin reduces proteinuria will be investigated.

描述（由申请人提供）：减少蛋白尿可减缓慢性肾病的进展。目前的护理标准是在不同水平上阻断肾素-血管紧张素系统以减少蛋白尿。然而，蛋白尿的减少通常是不完全的，因为参与蛋白尿发病机制或修饰的其他途径不受该疗法的影响。 PI 实验室的长期目标是开发基于新机制的治疗药物，以减少蛋白尿并减少因肾小球疾病引起的慢性肾病的进展。减少慢性肾病向终末期肾病的进展将对美国和全世界产生重大的积极社会和经济影响。 PI 实验室发现了循环糖蛋白血管生成素样 4 (Angptl4) 在人类和实验性肾病综合征中的重要作用。他的团队进行的研究表明，循环中的 Angptl4 是蛋白尿、低蛋白血症和高甘油三酯血症（肾病综合征的三个主要组成部分）之间的第一个分子联系。在肾小球疾病中，当蛋白尿变得中度至重度时（在人类情况下，当达到肾病范围时），骨骼肌、心脏、肝脏和脂肪组织的 Angptl4 分泌增加。循环中的Angptl4通过与肾小球内皮βvβ5整合素结合来减少蛋白尿，同时还通过抑制内皮结合脂蛋白脂肪酶的活性来诱导高甘油三酯血症。此外，Angptl4表达的这种多器官上调似乎是由于血浆游离脂肪酸/白蛋白比率的增加所致。 PI 开发了四种新的人类 Angptl4 蛋白突变形式，可减少局灶性和节段性肾小球硬化 (FSGS) 和糖尿病肾病大鼠模型中的蛋白尿，而不显着影响血浆甘油三酯水平。在具体目标 1 中，将使用器官特异性 PPAR 敲除小鼠进一步研究肾病综合征中血浆游离脂肪酸/白蛋白比率升高与外周器官 Angptl4 表达增加之间的关系。在具体目标 2 中，我们将测试每月两次施用突变型人 Angptl4 或从脂肪组织转基因表达大鼠 Angptl4 是否可以减少 FSGS 或糖尿病肾病大鼠模型中的肾小球硬化和慢性肾病的进展。在具体目标 3 中，将研究循环 Angptl4 与肾小球内皮 αvβ5 整合素相互作用减少蛋白尿的机制。