IMPAIRMENT OF UROMODULIN PROTEIN MATURATION IN HEREDITARY RENAL CYSTIC DISORDERS: CELLULAR AND ANIMAL MODELS FOR IDENTIFICATION OF THE PATHOGENETIC MECHANISMS TRIGGERED BY MUTANT ISOFORMS AND IMPLICATIONS FOR THE TREATMENT OF THESE DISORDERS

Chronic renal failure (CRF) affects 2 in a thousand people. It is characterised by a progressive, irreversible reduction of renal filtration ability. Among the major causes of CRF are renal cystic disorders, characterised by the presence in the kidney of fluid-filled tubule dilatations called cysts. There is no specific therapy for these disorders but dialysis followed by kidney transplantation when the kidneys are no longer able to function at a level that is necessary for day to day life. Medullary cystic kidney disease, familial juvenile hyperuricemic nephropathy and gluomerulocystic kidney disease are hereditary renal cystic disorders caused by mutations in the gene encoding uromodulin, the most abundant protein in urine. We have shown that mutant uromodulin maturation is impaired. Before being secreted by cells, proteins are properly folded in a cellular compartment called endoplasmic reticulum. If they are defective and cant be properly folded they are degraded. However, in pathologic conditions, they form bulky aggregates within the cell that can be toxic and lead to cell death. We have shown that mutant uromodulin is retained within the endoplasmic reticulum. Furthermore, we observed the presence of uromodulin aggregates within patient renal cells. These data suggest that uromodulin mutations cause a misfolding of the protein and this could eventually lead to death of renal tubular cells with a progressive damage of kidney function. In our project, we aim at the characterisation of the molecular mechanisms that lead to the formation of uromodulin aggregates and how the cells reacts to their presence. We will produce cellular and animal models by introducing the defective gene. The discovery of the mechanisms that lead to the pathological condition could allow the identification of potential targets for therapeutic intervention. Animal and cellular models could contribute to the validation of possible therapies for these yet untreatable disorders.