Characterization of the pathophysiologie of uromodulin-associated kidney disease

• Applicant: Dr. Elisabeth Gabriele Kemter
• Subject Area: Nephrology
• Term: from 2010 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 190229132

Uromodulin is expressed specifically in the kidney and is the most abundant protein in mammalian urine. Mutations within the uromodulin (UMOD) gene cause the heritable dominant disease called ‘uromodulin associated kidney disease (UAKD)’ in humans. The clinical symptoms of this disease are very heterogeneous and its pathogenesis is nearly unknown. Our recently established two Umod mutant mouse lines, exhibiting phenotypes highly similar to UAKD, already enabled the classification of Umod mutations as gain-of-toxic function mutations causing renal dysfunction and showed so far unknown new aspects of this disease. Based on our previous results, we aim to further characterize the pathophysiology of this disease. First, we hypothesize that there are mediators in blood responsible for alterations in energy metabolism. Further, cellular consequences of the trafficking defect of mutant uromodulin on the function of the endoplasmic reticulum (ER) will be analyzed, and our hypothesis will be tested, that application of molecular chaperons will ameliorate ER dysfunction and the trafficking defect of mutant uromodulin. This might represent a novel therapeutic strategy for UAKD. In addition, we will in detail examine the progression of the disease, which constantly results in end-stage renal disease in humans. Finally, analyses with our Umod mutant mouse lines will for the first time enable to answer the question, how Umod mutations cause renal cyst formation, which is a main feature of UAKD.

• DFG Programme: Research Grants