Role and Mechanisms of Epithelial Injury in Diabetic Nephropathy

描述（由申请人提供）： 糖毒性、脂毒性、晚期糖基化终产物（AGE）和活性氧（ROS）已成为糖尿病诱导的组织损伤的重要介质。然而，这些介质引起肾脏细胞损伤的精确细胞靶点和分子机制仍然不清楚。 肾小球（足细胞）和肾小管上皮细胞现在都成为糖尿病肾病（DN）中糖尿病诱导损伤的重要靶点。因此，足细胞耗竭最近已在1型（T1 DM）和2型（T2 DM）糖尿病患者中描述，并被认为是蛋白尿发生的强预测因子。此外，肾小管上皮细胞凋亡和上皮间质转化（EMT）可能是启动DN肾小管间质进展的基础。 我们目前的初步结果，提供了一个令人信服的理由，集中我们的研究计划，调查新出现的作用和机制，上皮细胞损伤的DN。具体来说，我们将测试两个新的假设：1。过氧化物酶体膜蛋白Mpv 17 l和/或Mpv 17是肾小球足细胞中抗氧化防御的必需调节剂，并保护免于糖尿病诱导的足细胞凋亡和足细胞耗竭（Bottinger，Mount Sinai）;和2. AGE和/或FFA的CD 36清道夫受体是AGE和/或FFA诱导的肾小管上皮损伤/凋亡和DN肾小管间质进展的重要介质（Susztak，AECOM）。 本提案的具体目标是测试： 1.过氧化物酶体膜蛋白是否调节足细胞中的抗氧化防御机制，并防止糖尿病诱导的ROS介导的足细胞损伤/凋亡 2.在糖尿病小鼠模型中，Mpv 17缺陷是否加速和增加足细胞凋亡和耗竭，导致进行性肾小球硬化和/或结节 3.其中CD 36依赖性细胞内途径信号AGE和FFA诱导肾小管上皮细胞损伤/凋亡 4. AGE结合蛋白CD 36和CD 38在近端肾小管的过度表达是否导致小鼠肾小管上皮细胞损伤/凋亡和DN肾小管间质进展的增加

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