Dietary interventions as therapeutic strategies in an ER-storage disease of the kidney

Mutations in the UMOD gene, encoding uromodulin, the most abundant urinary protein in physiological conditions, lead to autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD). This is a rare genetic disorder, characterized by tubulointerstitial damage and progressive loss of kidney function. To date, there is no specific therapy for ADTKD-UMOD, other than dialysis followed by transplantation. All UMOD mutations, likely by impacting on protein structure, lead to mutant uromodulin accumulation in the endoplasmic reticulum (ER) of producing cells.

Previous studies have already demonstrated the beneficial effects of specific dietary interventions in other conditions characterized by altered protein homeostasis and inflammation.

Stemming on preliminary data showing similar beneficial effects at an early stage of disease, in this project we aim at: 1) assessing the effectiveness of specific dietary interventions on ADTKD-UMOD pathogenesis at an advanced stage of the disease and the possibility that such treatments can even revert the already established kidney damage; 2) characterizing the molecular events activated upon dietary intervention that contribute to improve kidney function and disease phenotype; 3) testing the therapeutic effectiveness of pharmacological compounds mimicking functional effects of the identified beneficial dietary interventions.

The results obtained in this study may pave the way for the use of specific dietary interventions or therapies that mimic their effect in ADTKD-UMOD. Furthermore, our data will contribute to clarifying the pathogenetic mechanisms underlying the onset and progression of the disease.