Podocyte stress hypertrophy and depletion

描述（由申请人提供）：肾小球硬化是导致90%终末期肾病（ESKD）的常见病理过程，与糖尿病、高血压、IgA肾病、局灶节段性肾小球硬化（FSGS）、狼疮和其他肾小球疾病相关。在美国，这些疾病每年总共花费约180亿美元，发病率和死亡率都很高。它们的流行率正在上升，在少数民族人群中更为常见。它们影响儿童和成人，尽管ESKD是一种特殊的老年性疾病，ESKD治疗的平均发病年龄为64岁。这项工作的中心假设是肾小球硬化是由肾小球细胞类型之一足细胞的消耗引起的。在之前的拨款周期中，我们在大鼠身上开发了一种新的转基因模型系统，我们可以在事先选择的时间和数量上消耗足细胞。我们表明足细胞耗竭确实以剂量依赖的方式引起FSGS的所有特征。其次，我们开发了一种新的计数肾小球足细胞的方法。第三，我们已经证明了在高热量饮食的衰老过程中，肾小球增大如何导致足细胞的相对消耗，从而导致肾小球硬化，以及如何通过限制卡路里来预防这种情况。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到ESKD相关，这些新的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：足细胞耗损本身会导致全身性高血压和系膜扩张，这是人类早期肾小球硬化的重要病理组成部分。目的2：通过对细胞大小调控mTOR通路的转基因调控足细胞大小，验证足细胞增大能力的限制使肾小球更容易发生肾小球硬化，而足细胞增大能力的增强可防止肾小球硬化的假设。目的3：在两种肾小球硬化大鼠模型中验证足细胞表型改变的新概念，我们将其称为“适应”和“失代偿”，其基本概念是理解这一过程的生物学原理将使我们能够开发人类足细胞应激的标记物，以及在足细胞丧失和随之而来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.