Role and Mechanisms of Epithelial Injury in Diabetic Nephropathy

描述(由申请人提供)： 糖毒性、脂毒性、晚期糖基化终末产物(AGE)和活性氧自由基(ROS)已成为糖尿病组织损伤的重要介质。然而，这些介质导致肾脏细胞损伤的确切细胞靶点和分子机制仍不清楚。 目前，肾小球(足细胞)和肾小管上皮细胞都是糖尿病肾病(DN)中糖尿病损伤的重要靶点。因此，最近在1型(T1 DM)和2型(T2 DM)糖尿病患者中描述了足细胞耗竭，并被认为是发展为蛋白尿的强烈预测因素。此外，肾小管上皮细胞凋亡和上皮-间充质转化(EMT)可能是糖尿病肾病肾小管间质进展的基础。 我们提出的初步结果为我们的研究计划提供了一个令人信服的理论基础，重点是研究上皮细胞损伤在糖尿病肾病中的新兴作用和机制。具体地说，我们将检验两个新的假说：1.过氧体膜蛋白Mpv17l和/或Mpv17是肾小球足细胞抗氧化防御的重要调节因子，可以防止糖尿病诱导的足细胞凋亡和足细胞枯竭(Bottinger，Mountain Sinai)；以及2.CD36 AGE和/或FFA清道夫受体是AGE和/或FFA诱导的肾小管上皮损伤/凋亡和肾小管间质进展的重要调节因子(Susztak，AECOM)。 这项提案的具体目的是测试： 1.过氧酶体膜蛋白是否调节足细胞抗氧化防御机制，对糖尿病诱导的ROS介导的足细胞损伤/凋亡具有保护作用 2.糖尿病小鼠模型中mpv17缺乏是否加速和增加足细胞的凋亡和耗竭，导致进行性肾小球硬化和/或结节。 3.哪些CD36依赖的细胞内通路信号转导AGE和FFA诱导肾小管上皮细胞损伤/凋亡 4.肾小管近端AGE结合蛋白CD36和RAGE的过度表达是否导致小鼠糖尿病肾病肾小管上皮细胞损伤/凋亡和肾小管间质进展增加。

DESCRIPTION (provided by applicant): Glucotoxicity, lipotoxicity, advanced glycation end products (AGE), and reactive oxygen species (ROS) have emerged as important mediators of diabetes-induced tissue injury. However, the precise cellular targets and molecular mechanisms by which these mediators cause cellular injury in the kidney remain poorly defined. Both, glomerular (podocytes) and tubular epithelial cells are now emerging as important targets for diabetes-induced injury in diabetic nephropathy (DN). Thus, podocyte depletion has been described recently in humans with type 1 (T1DM) and type 2 (T2DM) diabetes, and is considered a strong predictor for the development of proteinuria. In addition, tubular epithelial apoptosis and epithelial-mesenchymal transition (EMT) may underlie the initiation of tubulointerstitial progression of DN. We present preliminary results that provide a compelling rationale to focus our research program on investigating the emerging role and mechanisms of epithelial cell injury in DN. Specifically, we will test two novel hypotheses: 1. The peroxisomal membrane proteins Mpv17l and/or Mpv17 are essential regulators of antioxidant defenses in glomerular podocytes and protect against diabetes-induced podocyte apoptosis and podocyte depletion (Bottinger, Mount Sinai); and 2. CD36 scavenger receptor for AGE and/or FFA is an essential mediator of AGE and/or FFA-induced tubular epithelial injury/apoptosis and tubulointerstitial progression of DN (Susztak, AECOM). The Specific Aims of this proposal are to test: 1. whether peroxisomal membrane proteins regulate antioxidant defense mechanisms in podocytes, and protect against ROS-mediated podocyte injury/apoptosis induced by diabetes 2. whether Mpv17-deficiency accelerates and increases podocyte apoptosis and depletion leading to progressive glomerulosclerosis and/or nodules in diabetic mouse models 3. which CD36-dependent intracellular pathways signal AGE and FFA induced tubular epithelial injury/apoptosis 4. whether proximal tubular overexpression of AGE binding proteins CD36 and RAGE leads to increased tubular epithelial injury/apoptosis and tubulointerstitial progression of DN in mice