The role of podocytes in the regulation of the single nephron glomerular filtration rate

足细胞在单肾单位肾小球滤过率调节中的作用

• 批准号: 192044013
• 负责人: Dr. Matthias Johannes Hackl
• 金额: --
• 依托单位: Keck School of Medicine
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/192044013?language=en
• 关键词: role; podocytes; regulation; single; nephron

The human kidney consists of 1 million small filtering units, the nephrons. Each nephron contains a glomerulus with a capillary tuft in which blood components are filtered. The kidney filter consists of three layers, the endothelium, the basement membrane and the slit diaphragm, which spans the distance between the podocyte foot processes. The filtration in each single nephron is regulated by alteration of the resistance of afferent and efferent vessels. The role of podocytes in regulation of the single nephron glomerular filtration rate hasn¿t been studied in detail so far. Oscillating calcium levels have been demonstrated in podocytes and they contain contractile element. This suggests, that podocytes contract on a regular basis. In my experiments I will study intact kidneys ofliving mice by multiphoton microscopy, this approach will allow to study morphology and function at the same time. I will visualize the fluctuations in intracellular calcium levels in podocytes by calcium-sensitive dyes. The podocytes will be loaded by an innovative technique of injecting the dyes selectively into the renal artery. To examine the influence of podocytes on glomerular filtration without confounding effects, I will use a genetically modified mouse with an artificial receptor (RASSL), whose expression is restricted to podocytes. Its activation rises intracellular calcium levels. To study podocyte morphology and calcium levels during disease states I will utilize two mouse models of focal segmental glomerulosclerosis (FSGS). The first model is the pharmaceutical induction of FSGS by injection of Adriamycin, the second one the genetic knockout of myosin 1E in a mouse. Both models lead to podocyte damage and loss. Using these mouse models I will look into reactions of neighboring podocytes to these insults.

人类肾脏由一百万个小的过滤单位肾单位组成。每个肾单位包含一个肾小球，肾小球内有毛细血管丛，血液成分在毛细血管丛中被过滤。肾脏滤过器由三层组成：内皮、基底膜和横跨足细胞足突之间距离的狭缝隔膜。每个肾单位的滤过受传入和传出血管阻力的改变调节。足细胞在调节单个肾单位肾小球滤过率中的作用至今尚未被详细研究。足细胞内钙离子水平存在振荡，含有收缩因子。这表明，足细胞定期收缩。在我的实验中，我将通过多光子显微镜研究活体小鼠的完整肾脏，这种方法将允许同时研究形态和功能。我将通过钙敏感染料观察足细胞内钙水平的波动。将通过将染料选择性地注射到肾动脉中的创新技术来装载足细胞。为了研究足细胞对肾小球滤过的影响而不产生混淆效应，我将使用具有人工受体（RASSL）的转基因小鼠，其表达仅限于足细胞。它的激活会升高细胞内钙水平。为了研究疾病状态下足细胞形态和钙水平，我将利用两种局灶节段性肾小球硬化（FSGS）小鼠模型。第一个模型是通过注射阿霉素药物诱导FSGS，第二个模型是在小鼠中基因敲除肌球蛋白1E。两种模型均导致足细胞损伤和损失。使用这些小鼠模型，我将研究邻近足细胞对这些损伤的反应。