Glomerular diseases are rare diseases. Nevertheless, they often lead to chronic renal failure and lifelong renal replacement therapy. We have shown, that in two forms of glomerular diseases, i.e. rapidly progressive glomerulonephritis (RPGN) and primary focal and segmental glomerulosclerosis (FSGS), glomerular epithelial cells get activated and that this results in loss of renal function. In addition, we have strong evidence that the epidermal growth factor (EGF) system is one of the major signaling pathways mediating activation of glomerular epithelial cells. In the present proposal, we will analyze the EGF system in vivo and in primary cells. We will use knock-out mouse models to analyze the relevance of the EGF system within glomerular cells. In a basic science approach, novel targets within the EGF system will be investigated. Regarding FSGS, we have identified a role of microRNA193 in podocytes. For RPGN, we will investigate cellular bridge formation, a crucial event in the disease. For the transition of pharmacological EGF inhibition to the clinical application, we will test in a macaque model of RPGN a novel recombinant decoy receptor against HB-EGF to reduce toxic side effects. For FSGS, the EGF system will be inhibited in an established rat model using specific EGF kinase inhibitors, which are already commercially available for cancer
patients. The ultimate goal of the present proposal is to prepare to step from bench to bedside and establish a novel therapeutic approach to treat some rare forms of glomerular diseases effectively and specifically.