The role of TNF-alpha and MAPkinase p38 for the development of proteinuric nephropathy in diabetes

TNF-α 和 MAPkinase p38 在糖尿病蛋白尿肾病发生中的作用

• 批准号: 231848071
• 负责人: Dr. Magdalena Woznowski
• 金额: --
• 依托单位: Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/231848071?language=en
• 关键词: role; TNF; alpha; MAPkinase; p38

Both the pro-inflammatory cytokine TNF-alpha (tumor necrosis factor-alpha), which is strongly induced by hyperglycaemia, as well as the MAP-kinase p38 (mitogen-activated kinase) participate in the signal transduction pathways leading to proteinuric kidney diseases. The exact molecular mechanism of this participation has not yet been identified. Our preliminary work showed that hyperglycaemia or TNF-alpha treatment induces the activation of p38 in podocytes, the epithelial cell type responsible for the formation of the glomerular slit diaphragm. Furthermore we could demonstrate that Nephrin, an essential protein component of the slit diaphragm, interacts with and is phosphorylated by p38. This hints at a molecular connection between the hyperglycaemia, activation of p38 and the induction of proteinuria and could be an important explanation for the pathomechanism. Therefore, the aim of this research project is to identify the detailed role and function of p38 in the generation of proteinuria and to establish the groundwork for a therapeutic intervention in a mouse model.

由高脂血症强烈诱导的促炎细胞因子TNF-α（肿瘤坏死因子-α）以及MAP-激酶p38（促分裂原活化激酶）均参与导致蛋白尿性肾病的信号转导途径。这种参与的确切分子机制尚未确定。我们的初步工作表明，高脂血症或TNF-α治疗诱导足细胞中p38的活化，足细胞是负责肾小球裂孔隔膜形成的上皮细胞类型。此外，我们可以证明，Nephrin，一个必不可少的蛋白质组成部分的狭缝隔膜，相互作用，并磷酸化的p38。这提示高血压、p38激活和蛋白尿的诱导之间存在分子联系，可能是对病理机制的重要解释。因此，本研究项目的目的是确定p38在蛋白尿产生中的详细作用和功能，并为小鼠模型的治疗干预奠定基础。

项目成果

Isolation of Glomeruli and In Vivo Labeling of Glomerular Cell Surface Proteins.

肾小球的分离和肾小球细胞表面蛋白的体内标记

• DOI: 10.3791/58542
• 发表时间: 2019
• 期刊: Journal of visualized experiments : JoVE
• 作者: Königshausen E;Potthoff SA;Haase R;Meyer-Schwesinger C;Kaufmann E;Rump LC;Stegbauer J;Sellin L;Quack I;Woznowski M
• 通讯作者: Woznowski M