Podocyte Injury in Diabetic Nephropathy

糖尿病肾病足细胞损伤

• 批准号: 7469958
• 负责人: MICHAEL R. VAUGHAN
• 金额: $ 12.73万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7469958
• 关键词: A Mouse; Animals; Apoptosis; Apoptotic; Applications Grants; Cells; Chronic; Cicatrix; Clinical; Cyclin-Dependent Kinases; Development; Diabetes Mellitus; Diabetic Nephropathy; Diphtheria Toxin; Disease; Effectiveness; Endothelial Cells; Event; Glucose; Goals; Human; In Situ; In Vitro; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Diseases; Kidney Failure; Lead; Link; Mediating; Mediator of activation protein; Modeling; Mus; Necrosis; Numbers; Physiological; Process; Proliferating; Protein Kinase C; Proteins; Proteinuria; Rate; Renal function; Role; Signal Pathway; Testing; Transgenic Organisms; Tretinoin; Vitamin A; citrate carrier; cyclin-dependent kinase inhibitor 1B; density; design; diabetic; glomerular basement membrane; glomerular filtration; glomerulosclerosis; human study; in vivo; mouse model; mutant; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; podocyte; prevent; response; tool

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is the most frequent cause of renal failure in the US. Human studies show that the loss of a specific glomerular cell, the podocyte, underlies the development of proteinuria and glomerular scarring in DN, both events leading to renal failure. One process leading to podocyte loss is in-situ apoptosis. Recent animal studies revealed that podocyte apoptosis is an early feature in diabetes nephropathy. However, the mechanisms that cause podocyte apoptosis are not well understood. In this grant proposal, we propose to investigate factors and mechanisms leading to podocyte apoptosis and to determine the relationship with the development of diabetic nephropathy. In the first aim, we will investigate in vitro and in vivo mechanisms leading to podocyte apoptosis in diabetes. First, we will examine the in vitro mechanisms leading to high glucose mediated podocyte apoptosis using an immortalized human podocyte line and an immortalized mouse podocyte line. .Second, we will investigate the effects of physiologic and pharmacologic insulin levels on in vitro podocyte apoptosis. Then we will explore the role of Protein-kinase C (PKC) in mediating high glucose induced apoptosis both in vitro and in vivo. In the second specific aim, we propose to investigate factors that influence the podocyte apoptotic response. We will test the hypothesis that the cyclin-dependent kinase p27 is protective against podocyte apoptosis in vitro and in vivo. Next we will focus on the effect of matricellular proteins on glucose-induced apoptosis in vitro. Finally, we will investigate the anti-apoptotic effects of a vitamin A derivative called all-trans retinoic acid (ATRA) on podocyte high glucose mediated apoptosis in vitro. While podocyte number has been linked with the development of DN, we propose to further correlate this relationship through the use of a trangenic mouse in which the podocyte number can be selectively reduced. Accordingly in the third specific aim, we will induce diabetes in mice with a lower podocyte number and compare progression to their littermates as controls. Secondly, we will utilize this model as a tool to develop a mouse model more consistent with human DN. Finally, using this model, we will test the effectiveness of ATRA in slowing the progression to diabetic nephropathy. These proposed studies investigate the mechanisms leading to podocyte loss via apoptosis in DN with the goal to better understand this disease process, develop a new mouse model of DN, and lead to targeted therapies that slow the development and progression of DN.

描述（由申请人提供）： 糖尿病性肾病（DN）是美国肾衰竭的最常见原因。人类研究表明，特定肾小球细胞的丧失是蛋白尿和DN中肾小球疤痕的发展，这两个事件都导致了肾衰竭。导致足细胞损失的一个过程是原位凋亡。最近的动物研究表明，足细胞凋亡是糖尿病肾病的早期特征。但是，引起足细胞凋亡的机制尚不清楚。在这项赠款建议中，我们建议研究导致足细胞凋亡的因素和机制，并确定与糖尿病肾病的发展的关系。 在第一个目标中，我们将研究导致糖尿病足细胞凋亡的体外和体内机制。首先，我们将使用永生的人足细胞系和永生的小鼠足细胞系来检查导致高葡萄糖介导的足细胞凋亡的高葡萄糖介导的足细胞凋亡。第二，我们将研究生理和药理学胰岛素水平对体外足细胞凋亡的影响。然后，我们将探讨蛋白激酶C（PKC）在体外和体内介导高葡萄糖诱导凋亡的作用。 在第二个特定目的中，我们建议研究影响足细胞凋亡反应的因素。我们将检验以下假设：细胞周期蛋白依赖性激酶p27在体外和体内具有保护性的podocyte凋亡。接下来，我们将重点介绍母细胞蛋白对体外葡萄糖诱导凋亡的影响。最后，我们将研究一种称为全反式视黄酸（ATRA）对足体高葡萄糖介导的体外细胞凋亡的维生素A衍生物的抗凋亡作用。 虽然足细胞数与DN的开发相关，但我们建议通过使用跨齿小鼠进一步关联这种关系，在该小鼠中可以选择性地减少Podocyte数量。因此，在第三个特定目的中，我们将诱导小鼠数量较低的小鼠中的糖尿病，并将进展与窝窝的进展为对照。其次，我们将使用此模型作为工具，以开发与人类DN更一致的鼠标模型。最后，使用此模型，我们将测试ATRA在减慢糖尿病肾病进展方面的有效性。 这些提出的研究研究了导致DN中细胞凋亡导致足细胞丧失的机制，其目标是更好地了解这种疾病过程，开发新的小鼠模型，并导致靶向疗法减慢DN的发育和进展。