Renal Protective Effects of Circulating Angiopoietin-like-4

循环血管生成素样 4 的肾脏保护作用

• 批准号: 9002042
• 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
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-10 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9002042
• 关键词: ANGPTL4 gene; Adipose tissue; Affect; Albumins; 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; Health; 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; 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; lipoprotein lipase; mutant; novel; overexpression; podocyte; protective effect; social; standard of care; uptake; urinary

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 αvß5 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 αvß5 integrin reduces proteinuria will be investigated.

描述（通过应用提供）：减少蛋白尿会减慢慢性肾脏疾病的进展。当前的护理标准是在各种水平上阻止肾素 - 血管紧张素系统，以减少蛋白尿。然而，蛋白尿的降低通常不完整，因为与这种疗法有关蛋白尿的发病机理或修饰的其他途径不受这种疗法的影响。 PI实验室的长期目标是开发基于新机制的治疗剂，这些治疗剂将减少蛋白尿并减少由于肾小球疾病而导致的慢性肾脏疾病的进展。减少慢性肾脏疾病到末期肾脏疾病的进展将在美国和全球范围内产生重大积极的社会和财务影响。 PI的实验室发现了人类和实验性肾病综合征中循环糖蛋白血管蛋白样-4（Angptl4）的主要作用。他的团队进行的研究表明，循环ANGPTL4是蛋白尿，低珠蛋白血症和高甘油三酸酯血症，这是肾病综合征的三个主要成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（在人类的情况下，达到肾病范围）时，就会发生骨骼肌，心脏，肝脏和脂肪组织的ANGPTL4分泌增加。循环ANGPTL4通过与肾小球αVß5整联蛋白结合来降低蛋白尿，同时还通过抑制森植物结合的脂蛋白脂肪酶的活性来诱导高甘油三酸酯。此外，似乎这种多器官上调ANGPTL4表达是由于血浆游离脂肪酸 /白蛋白比的增加而导致的。 PI开发了四种新的突变形式的人类Angptl4蛋白，可在局灶性和节段性肾小球硬化症（FSGS）和糖尿病性肾病的大鼠模型中降低蛋白尿症，而没有显着影响血浆甘油三酸酯水平。在特定的目标1中，使用器官特定的PPAR基因敲除小鼠，将进一步研究肾病综合征中升高的血浆无脂肪酸 /白蛋白比与外周器官Angpt4表达之间的关系。在特定的目标2中，我们将测试是否每月两次给予突变的人ANGPTL4，或者是脂肪组织中大鼠Angptl4的转基因表达可以减少肾小球硬化和慢性肾脏疾病在FSGS模型或糖尿病肾病大鼠模型中的进展。在特定的目标3中，将研究循环ANGPTL4与肾小球内皮αVß5整合蛋白相互作用的机制。