Diabetic nephropathy (DN) is one of the most severe and life-threatening complications of diabetes mellitus. About 30% of patients with type 2 diabetes will eventually develop DN. Duration of diabetes as well as glycaemicand blood pressure control do not s ufficiently explain the risk of developing DN. About 31 genes have been reported to possibly contribute to DN susceptibility. A major susceptibility gene was mapped to 18q and a sequence variant in the CNDP1 gene was identified to cause a 3-fold elevated risk of DN. On the proteomic level, protein modifications by advanced glycation end-products (AGEs) are known to be sufficient to cause DN. AGEs are closely linked to reactive oxygen species (ROS) production. Different variables promise to have the poten tial of serving as biomarkers with high predictive value for DN risk assessment. To achieve the goals of the programme calling for identification of pathophysiological relevant genes and biomarkers correlated with onset, progression and response to therapy of DN, the project focuses on prospective research and case-control studies to: - Systematically re-evaluate available genetic data - Perform functional genomics for studying effects of gene variants - Study the influence of AGEs, ROS and carnosine a nd further predictive biomarkers. The latter will be realized both on the genomic (expression profiling in kidney biopsies) and proteomic level (mass-spectometry). In 3 multivariate analyses these markers will be correlated with the success of treatment wi th ACE inhibitors, irbesartan, and benfotiamine. A risk model will be developed for use by clinicians, who will evaluate the model prospectively in the future. This proposal will have significant impact on patient care. It is expected to provide scientif ic evidence for novel individualized therapeutic approaches. Although there is a focus on DN, the effects of DN-related markers on retinopathy will also be studied.
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