Kidney Keratins, endogenous cytoprotective factors?

角蛋白(K)是一种中间丝(IF)，是上皮细胞细胞骨架的主要组成部分，为其提供机械完整性。角蛋白在各种压力情况下也具有细胞保护功能，最适用于皮肤和胃肠道。肾小管上皮细胞(TEC)是肾上皮细胞中含量最丰富的细胞。在几乎所有的肾脏疾病中，TEC都暴露在许多应激刺激下，它们通过表型改变和细胞骨架重塑对这些刺激做出反应。我们最近发现，主要的肾角蛋白K7、K8、K18和K19在不同的动物模型和肾损伤患者中高度上调，可以作为TEC应激的新标记物。我们推测，角蛋白可能在TEC适应一系列应激情况的过程中发挥主要的细胞保护作用，并促进TEC的修复。我们的目标是在以下工作包中解决这一假说：1.我们将比较野生型和各种角蛋白缺陷的原代小鼠TEC在生物力学特性、表型和促炎改变、再生潜力和存活率方面的差异。在体内，我们将分析整个角蛋白II基因簇在TEC中的特异性缺失或健康小鼠中单一主要肾角蛋白的缺失，以及在以TEC损伤和再生为特征的几种肾脏疾病模型中的后果。3.我们将使用K8-EYFP报告小鼠来分析角蛋白细丝的体外和活体动力学。最后，我们的目标是确定翻译后修饰和潜在的新的肾角蛋白，并测试角蛋白作为TEC损伤的特异性尿标记物的有用性。这些实验将为肾角蛋白的功能作用和诊断潜力提供第一批数据。

Keratins (K) are intermediate filaments (IFs) and a major component of the cell cytoskeleton of epithelial cells, providing for their mechanical integrity. Keratins also have cytoprotective functions in a variety of stress situations, best described for skin and the gastrointestinal tract. Tubular cells (TEC) are the most abundant renal epithelial cells. During virtually all kidney diseases TEC are exposed to a number of stress stimuli, to which they react by phenotypic alterations and cytoskeletal remodeling. We recently showed that the major renal keratins, i.e. K7, K8, K18 and K19, are highly up-regulated in different animal models and patients with kidney injury and could serve as novel markers of TEC stress. We hypothesize, that keratins may play a major cytoprotective role during the accommodation of TEC to a broad array of stress situations and that they promote TEC repair. We aim to tackle this hypothesis in the following work packages:1. We will compare wild-type and various keratin-deficient primary murine TEC in vitro with respect to biomechanical properties, phenotypic and pro-inflammatory alterations, regenerative potential and survival.2. In vivo, we will analyze the consequences of deletion of the whole keratin II gene cluster specifically in TEC or of single major renal keratins in healthy mice and in several renal disease models characterized by TEC injury and regeneration. 3. We will use the K8-eYFP reporter mice to analyze the dynamics of keratin filaments in vitro and in vivo.4. Finally, we aim to identify the post-translational modifications and potential novel kidney keratins and test the usefulness of keratins as specific urinary markers of TEC injury.These experiments will provide first data on the functional role and diagnostic potential of renal keratins.