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Nephrin in proteinuric diseases development of diagnostics, prognostic and treatement modalities

Deliverables

The main findings of the PROTEINURIC DISEASES project include the following: - Nephrinuria as a possible prognostic marker of susceptibility for kidney complications in diabetes: Fragments of the podocyte protein nephrin were found in the urine of type I diabetic patients. One third of the patients were nephrinuric while the control subjects were negative suggesting that the glomerular filtration barrier and the slit diaphragm are affected by diabetes. As this is observed before major kidney damage as measured by albuminuria, nephrinuria may be an early marker for the diabetic damage. Diabetic nephropathy is devastating chronic event that is characterized by persistent proteinuria, elevated blood pressure and decline in renal function. Nephrinuria could be used as a specific diagnostic marker to profile different patient groups and optimise pharmacological interventions. - Circulating nephrin autoantibodies in the patients with type I diabetes indicating early glomerular damage: Patients with the juvenile onset diabetes typically present with autoantibodies to the undefined complex of the islets of langerhans in the pancreas. Since our results had shown the unexpected presence of nephrin also in pancreas we hypothesized that nephrin is one of the target autoantigens and, after the autoantibody production during early destruction stage in diabetes, could yield circulating antinephrin autoantibodies finally finding its epitope in the kidney with damaging consequences. We could find circulating autoantibodies against nephrin from the patients with diabetic nephropathy. This study will continue to analyse the further characteristics of the patients with circulating autoantibodies and nephropathy in detail.
The main findings of the PROTEINURIC DISEASES project include the following: - Genetic knockout models of nephrin: To study the basic physiologic function of nephrin, we have generated a nephrin deficient mouse line. The nephrin deficient mice show early postnatal lethality and morphology typical to proteinuric diseases. Thus it provides an important tool to study nephrin and its associate proteins in different developmental stages of proteinuria. - The nephrin antisense transcript expression: By using bioinformatics we have found a naturally occurring antisense transcript of nephrin in the mouse. Our data suggest that the nephrin antisense may regulate nephrin expression and thus be an important level to regulate the level of functional nephrin in the kidney. - Gene expression profiles of the kidney diseases: To get a practical aspect on gene expression in proteinuric stages of renal disease, cDNA arrays were used to compare the gene expression in healthy and diseased kidneys. On that basis, hand-picked genes showing appreciable up/downregulation were chosen to describe diagnostic kidney biopsies and their applicability as diagnostic tools.
The main findings of the PROTEINURIC DISEASES project include the following: - Proteins interacting with nephrin: With this project, we have expanded the current knowledge of the molecular structure of the kidney filtration barrier in describing additional nephrin binding molecules, CD2 associated protein and densin. In addition to these, two new interacting molecules have been found and are being analysed further. - Nephrin dysregulation leads to the development of proteinuria: Our results show that the amount of nephrin protein decreases in various kidney diseases. For the studies we have used experimental models mimicking kidney glomerular diseases and human kidney biopsies of various diagnostic groups. In all these nephrin mRNA and protein levels are regulated in a typical way. In addition, we have shown that inflammatory cytokines involved in kidney diseases increase the amount of nephrin expression. It appears that nephrin dysregulation in the kidney is centrally involved in the pathogenesis in kidney diseases expressing with protein loss in the urine. - The role of novel podocyte cytoskeletal proteins in the development of proteinuria: We have localized by immunoelectron microscopy new proteins to kidney glomerular epithelial cells. These proteins are involved in maintaining the functional integrity of the cytoskeleton in podocytes. In addition, we have shown that they may have a role in glomerular diseases.