Renal Protective Effects of Circulating Angiopoietin-like-4

描述(申请人提供)：减少蛋白尿可以延缓慢性肾脏疾病的进展。目前的护理标准是在不同水平阻断肾素-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整的，因为参与蛋白尿发病或修改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新的基于机制的治疗剂，以减少蛋白尿，并减少由于肾小球疾病而导致的慢性肾脏疾病的进展。减少慢性肾脏疾病的进展到终末期肾脏疾病将在美国和世界范围内产生重大的积极的社会和财政影响。PI的实验室已经发现循环糖蛋白Angiopoietin-like-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，循环中的ANGPTL4是蛋白尿、低蛋白血症和高甘油三酯血症之间的第一个分子联系，这三个因素是肾病综合征的三个主要组成部分。在肾小球疾病中，当蛋白尿变得中度到重度时(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ANGPTL4通过与肾小球内皮细胞αv？5整合素结合减少蛋白尿，同时也通过抑制内皮结合脂蛋白脂酶活性诱导高甘油三酯血症。此外，ANGPTL4的这种多器官表达上调似乎是由于血浆游离脂肪酸/白蛋白比率增加所致。PI已经开发出四种新的人ANGPTL4蛋白突变形式，可以在不显著影响血浆甘油三酯水平的情况下减少局灶性和节段性肾小球硬化(FSGS)和糖尿病肾病大鼠的蛋白尿。在具体目标1中，将利用器官特异性PPAR基因敲除小鼠进一步研究肾病综合征患者血浆游离脂肪酸/白蛋白比值升高与外周器官ANGPTL4表达增加的关系。在具体目标2中，我们将测试每月两次给药突变的人ANGPTL4，或者脂肪组织中转基因表达的大鼠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脏疾病的进展。在具体目标3中，将研究循环血管紧张素样生长因子4与肾小球内皮细胞αv？5整合素相互作用降低蛋白尿的机制。

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.