Podocyte stress hypertrophy and depletion

描述（由申请人提供）：肾小球硬化是一种常见的病理过程，90%的终末期肾病（ESKD）与糖尿病、高血压、伊加肾病、局灶性节段性肾小球硬化（FSGS）、狼疮和其他肾小球疾病相关。这些疾病在美国每年总共花费约180亿美元，并且具有高发病率和死亡率。它们的流行率正在上升，在少数群体中更为常见。它们影响儿童和成人，尽管ESKD特别是一种老年疾病，ESKD治疗的平均发病年龄为64岁。这项工作的核心假设是肾小球硬化是由肾小球细胞类型之一，足细胞的耗竭引起的。在先前的资助周期中，我们在大鼠中开发了一种新的转基因模型系统，在该系统中，我们可以在事先选择的时间和数量消耗足细胞。我们表明，足细胞耗竭确实导致FSGS的所有功能，在剂量依赖性的方式。其次，我们建立了一种新的肾小球足细胞计数方法。第三，我们已经展示了在高热量饮食的衰老过程中肾小球扩大如何导致相对的足细胞耗竭，从而易患肾小球硬化症，以及如何通过限制热量来预防。因为我们知道高血压通常与肾小球硬化和肾小球硬化进展为ESKD相关，所以这些新工具和概念将用于测试与人类肾小球硬化相关的特定假设：目的1：足细胞耗竭本身引起系统性高血压和系膜扩张，系膜扩张是人类早期肾小球硬化的重要病理组成部分。通过使用细胞大小控制的mTOR途径的转基因来调节足细胞大小，检验以下假设：足细胞大小增加的能力的限制使得肾小球更容易受到肾小球硬化症的影响，而足细胞大小增加的能力的增强防止肾小球硬化症。目标3：我们在两种肾小球硬化大鼠模型中提出了足细胞表型改变的新概念，即我们称之为“适应”和“失代偿”的应激反应，其基本概念是理解这一过程的生物学将使我们能够开发人类足细胞应激的标志物，以及在足细胞应激导致足细胞丧失和随后的肾小球硬化之前治疗和预防足细胞应激的新方法。

DESCRIPTION (provided by applicant): Glomerulosclerosis is the common pathologic process responsible for 90% of End Stage Kidney Disease (ESKD) associated with diabetes, hypertension, IgA nephropathy, Focal Segmental Glomerulosclerosis (FSGS), lupus and other glomerular diseases. Together these diseases cost approximately $18 billion per year in the US, and carry high morbidity and mortality. They are increasing in prevalence and are commoner in minority populations. They affect both children and adults, although ESKD is particularly a disease of aging with average onset of ESKD treatment at 64 years. The central hypothesis underlying this work is that glomerulosclerosis is caused by depletion of one of the glomerular cell types, the podocyte. During the prior grant cycle we developed a new transgenic model system in the rat where we can deplete podocytes by an amount and at a time of prior choosing. We show that podocyte depletion does indeed cause all the features of FSGS in a dose-dependant manner. Second we have developed a new method for counting podocytes in glomeruli. Third, we have shown how glomerular enlargement during aging on a high calorie diet causes relative podocyte depletion that predisposes to glomerulosclerosis, and how this can be prevented by calorie restiction. Because we know that hypertension is commonly associated with glomerulosclerosis and progression of glomerulosclerosis to ESKD, these new tools and concepts will be used to test specific hypotheses relevant to human glomerulosclerosis: Aim 1: Podocyte depletion itself causes systemic hypertension and mesangial expansion, an important pathologic component of early glomerulosclerosis in man. Aim 2: Test the hypothesis that limitation of the ability of the podocyte to increase in size makes the glomerulus more susceptible to glomerulosclerosis, while enhancement of podocyte's ability to increase in size prevents glomerulosclerosis, by using transgenes of the mTOR pathway of cell size control to modulate podocyte size. Aim 3: Validate the novel concepts of podocyte alteration in phenotype in response to stress that we have termed "adaptation" and "decompensation" in two rat models of glomerulosclerosis, with the underlying concept that understanding the biology of this process will allow us to develop markers for human podocyte stress as well as new approaches to treat and prevent podocyte stress before it results in loss of podocytes and consequent glomerulosclerosis.