CD80 Expression on Podocytes and the Pathogenesis of Minimal Change Disease

描述(由申请人提供)：微小病变病(MCD)是儿童中最常见的肾病综合征，可与显著的发病率相关。目前MCD的病因尚不清楚，但它可能是由于一种循环因子，可能由活化的T细胞释放，导致足细胞功能障碍，导致肾炎性蛋白尿发展过程中肾小球通透性的改变。我们的小组假设，MCD是由足细胞的表型变化所介导的，在足细胞中表达CD80，然后随着足细胞的形状变化，CD80被排入尿液。在初步数据中，我们发现活动期(复发)MCD患者尿CD80水平升高，正常人、缓解期MCD和局灶节段性肾小球硬化的蛋白尿受试者尿CD80水平均不存在。我们还在有限数量的MCD患者的肾活检组织中发现了足细胞中的CD80。我们还开发了一种MCD的体外模型，在该模型中，我们可以激活存在于培养的人足细胞上的Toll样受体，并表明它通过CD80的表达、形状改变(肌动蛋白重排)和突触素的丢失来激活干扰素和NF：B依赖的通路，我们可以用皮质类固醇(临床上用于治疗微小病变的疾病)来挽救这一点。在这项应用中，我们将首先进行细胞培养研究，以评估患有和不患有MCD的受试者的血清和外周血单个核细胞培养上清液在体外刺激CD80表达的潜在作用，确定Toll样受体配体在体外刺激足细胞CD80的细胞信号通路，并基于这些发现建立MCD的动物模型。其次，我们将进行更多的临床研究，以确定与其他肾小球疾病相比，CD80在MCD中的特异性、时间排泄和足细胞表达。我们还将研究CTLA-4的尿液排泄和足细胞表达，我们假设CTLA-4是自动调节CD80反应的因素。我们希望这些研究不仅能阐明微小病变病的病因，还能揭示新的治疗和预防策略。 公共卫生相关性：微小病变疾病是儿童肾病综合征最常见的原因，并导致广泛的发病率。这项提案中概述的研究旨在确定导致这种疾病的潜在机制，并确定是否可以开发一种更好的非侵入性方法来诊断这种疾病。这些研究不仅将提供对这种情况的原因的见解，而且还可能为治疗提供新的靶点和策略。

DESCRIPTION (provided by applicant): Minimal change disease (MCD) is the most common nephrotic syndrome in children, and can be associated with marked morbidity. Currently the etiology of MCD is unknown, but it has been hypothesized to be due to a circulating factor, possibly released by activated T cells, that induces podocyte dysfunction, resulting in an alteration of glomerular permeability with the development of nephrotic proteinuria. Our group has hypothesized that MCD is mediated by a phenotypic change in podocytes in which they express CD80, which is then shed into the urine as the podocyte undergoes shape change. In preliminary data we have found elevated levels of urinary CD80 in patients with active (relapsing) MCD and that it is absent in normal individuals, in MCD in remission, and in proteinuric subjects with focal segmental glomerulosclerosis. We have also identified CD80 in podocytes of limited numbers of renal biopsies of subjects with MCD. We have also developed an in vitro model of MCD in which we can activate toll-like receptors present on cultured human podocytes and show that it activates interferon and NF:B dependent pathways with the expression of CD80, shape change (actin rearrangement) and loss of synaptopodin, and we can rescue this with corticosteroids (which are used clinically to treat minimal change disease). In this application we will first perform cell culture studies to evaluate the potential role of serum and peripheral blood mononuclear leukocyte supernatants from subjects with and without MCD in stimulating CD80 expression in vitro, to determine the cellular signaling pathways by which Toll-like receptor ligands stimulate CD80 in podocytes in vitro, and to develop an animal model of MCD based on these findings. Second, we will perform additional clinical studies to determine the specificity, temporal excretion and podocyte expression of CD80 in MCD compared to other glomerular disorders. We will also examine the urinary excretion and podocyte expression of CTLA-4 for which we hypothesize is the factor that autoregulates the CD80 response. It is our hope that these studies may elucidate not only the cause of minimal change disease but also reveal new strategies for treatment and prevention. PUBLIC HEALTH RELEVANCE: Minimal change disease is the most common causes of nephrotic syndrome in children and causes extensive morbidity. The studies outlined in this proposal are aimed at identifying both the underlying mechanism driving this disease and also determining if one can develop a better and noninvasive means for diagnosing this disease. These studies will not only provide insights into the cause of this condition, but may also provide new targets and strategies for treatment.