Renal Protective Effects of Circulating Angiopoietin-like-4

描述（由申请人提供）：减少蛋白尿可减缓慢性肾脏疾病的进展。目前的治疗标准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，蛋白尿的减少往往是不完全的，因为参与蛋白尿发病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，以减少蛋白尿和减少肾小球疾病引起的慢性肾脏疾病的进展。减少慢性肾脏疾病的进展到终末期肾脏疾病将对美国和全世界产生重大的积极的社会和经济影响。PI的实验室已经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主要作用。他的团队进行的研究表明，循环Angptl4是蛋白尿、低白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，当蛋白尿变为中度至重度时，骨骼肌、心脏、肝脏和脂肪组织的Angptl4分泌增加（在人类环境中，当蛋白尿达到肾病范围时）。循环Angptl4通过与肾小球内皮细胞结合减少蛋白尿。5整合素，同时也通过抑制内皮结合脂蛋白脂肪酶的活性诱导高甘油三酯血症。此外，Angptl4表达的多器官上调似乎是由血浆游离脂肪酸/白蛋白比的增加引起的。PI已经开发了四种新的人类Angptl4蛋白突变形式，可以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，而不会显著影响血浆甘油三酯水平。在Specific Aim 1中，我们将使用器官特异性PPAR敲除小鼠进一步研究肾病综合征患者血浆游离脂肪酸/白蛋白比值升高与周围器官Angptl4表达升高之间的关系。在Specific Aim 2中，我们将测试每月两次给药突变的人类Angptl4，或从脂肪组织中转基因表达大鼠Angptl4是否可以减少FSGS或糖尿病肾病大鼠模型的肾小球硬化和慢性肾病的进展。在Specific Aim 3中，循环Angptl4与肾小球内皮细胞相互作用的机制？整合素减少蛋白尿将被研究。

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.