CELLULAR AND ANIMAL MODELS FOR THE IDENTIFICATION OF THE PATHOGENETIC MECHANISMS IN UROMODULIN-ASSOCIATED RENAL CYSTIC DISORDERS

Chronic renal failure (CRF) affects 2 in a thousand people. It is characterised by a progressive, irreversible decrease 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 more able to function at a level that is necessary for quotidian 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. In order to be functional, proteins need to be properly folded. Changes inside a protein can interfere with its folding and lead to protein degradation. However, in pathologic conditions they form intracellular aggregates that can be toxic and induce cell death. We have shown that mutant uromodulin is retained in the endoplasmic reticulum where folding takes place. Moreover, uromodulin aggregates were observed within patient renal cells. These data suggest that uromodulin mutations cause a misfolding of the protein that 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 uromodulin aggregation and of the following cell response. In particular we will use cells derived from the specific part of the nephron expressing endogenous uromodulin. Furthermore, to be closer to the patient condition, we have produced a mouse model expressing the mutated 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 would be an ideal tool to test therapeutic molecules for these yet untreatable disorders.