MOLECULAR MECHANISMS OF PATHOGENESIS AND PRECLINICAL TREATMENT IN RENAL DISORDERS ASSOCIATED WITH UROMODULIN MUTATIONS

The aim of the research

Main researcher LUCA RAMPOLDI

Uromodulin associated kidney disease (UAKD) is an hereditary renal disease caused by mutations in the gene encoding uromodulin, the most abundant protein secreted in the human urine.

UAKD is characterized by a progressive damage of renal tubules and interstitium, development of renal cysts, alteration of urine concentrating ability and progressive loss of renal function. Currently, there are no specific therapies for UAKD other than dialysis followed by kidney transplantation when the kidneys are no more able to function at a level that is necessary for quotidian life. In order to understand the molecular bases of the disease, in the lab we have set up cellular models that express different mutant uromodulin isoforms and generated a mouse model that recapitulates most of the features observed in UAKD patients. In order to be functional, proteins need to be properly folded. Changes inside a protein can interfere with its folding and, in pathologic conditions, they can lead to toxic effect for the cell. We have shown that mutant uromodulin is retained in the endoplasmic reticulum, where protein folding takes place. In the mouse model, this primary effect of uromodulin mutations is associated with progressive activation of the inflammatory, fibrotic process that eventually results in tissue damage. In our project, integrating information from cellular models derived from the specific part of the nephron expressing endogenous uromodulin, animal models and patient biological samples, we aim at identifying the mechanisms that are the bases of the disease. Therapies will be designed relying on current knowledge of the disease and on results that will be generated through this study and will be tested in cell and mouse model. Positive results could pave the way to the identification of treatments that could be transferred into clinical practice and could have a significant impact on the quality of life of UAKD patients.

Scientific publications

2016 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AME
A structured interdomain linker directs self-polymerization of human uromodulin