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

高血糖强烈诱导的促炎性细胞因子肿瘤坏死因子-α和丝裂原活化蛋白激酶p38均参与了导致蛋白尿肾病的信号转导通路。这种参与的确切分子机制尚未确定。我们的初步工作表明，高血糖或肿瘤坏死因子-α治疗诱导足细胞中p38的激活，足细胞是导致肾小球裂隙隔膜形成的上皮细胞类型。此外，我们还可以证明，作为缝隙隔膜的重要蛋白质成分，NePhin与p38相互作用，并被p38磷酸化。这提示高血糖、p38的激活与蛋白尿的诱导之间存在分子联系，这可能是发病机制的一个重要解释。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，并为在小鼠模型中进行治疗干预奠定基础。

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.