Renal Protective Effects of Circulating Angiopoietin-like-4

描述（由申请人提供）：减少蛋白尿减缓慢性肾脏疾病的进展。目前的标准治疗是阻断不同水平的肾素-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改变的其他途径不受这种治疗的影响。PI实验室的长期目标是开发新的基于机制的治疗药物，以减少蛋白尿并减少肾小球疾病引起的慢性肾脏疾病的进展。减少慢性肾脏疾病向终末期肾脏疾病的进展将在美国和世界范围内产生重大的积极社会和经济影响。PI的实验室已经发现循环糖蛋白血管生成素样-4（Angptl 4）在人类和实验性肾病综合征中的主要作用。他的团队进行的研究表明，循环Angptl 4是蛋白尿、低白蛋白血症和高胆固醇血症（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（在人类背景下，当其达到肾病范围时），骨骼肌、心脏、肝脏和脂肪组织的Angptl 4分泌增加。循环Angptl 4通过结合肾小球内皮α v β 5整联蛋白减少蛋白尿，同时还通过抑制内皮结合脂蛋白脂酶的活性诱导高脂血症。此外，似乎Angptl 4表达的这种多器官上调是由血浆游离脂肪酸/白蛋白比率的增加引起的。PI已经开发了四种新的突变形式的人Angptl 4蛋白，其在局灶性和节段性肾小球硬化（FSGS）和糖尿病肾病的大鼠模型中减少蛋白尿，而不显著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升高的血浆游离脂肪酸/白蛋白比率与增加的外周器官Angptl 4表达之间的关系。在具体目标2中，我们将测试在FSGS或糖尿病肾病的大鼠模型中，每月两次施用突变的人Angptl 4或从脂肪组织转基因表达大鼠Angptl 4是否可以减少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Angpt 14与肾小球内皮α v β 5整联蛋白的相互作用减少蛋白尿的机制。

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.