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

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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.