Calorie restriction leads to degradation of mutant uromodulin and ameliorates inflammation and fibrosis in UMOD-related kidney disease

BackgroundMutations in UMOD, encoding uromodulin, lead to Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD), a genetic cause of kidney failure. UMOD mutations have a common gain-of-toxic-function effect, causing mutant uromodulin retention in the endoplasmic reticulum (ER). This leads to ER stress, alteration of protein homeostasis and mitochondrial dynamics, defective autophagy and increased cell death. Calorie restriction (CR) exerts a beneficial role in diseases characterized by accumulation of pathogenic protein and inflammation, by modulating several pathways, including autophagy induction and suppression of inflammation and fibrosis. Given the relevance of these features in ADTKD, we investigated the effect of CR on disease onset and progression. MethodsTransgenic mice expressing C147W uromodulin (TgUmodC147W) were subjected to a moderate (30%) CR regimen for 15 or 24 weeks, starting at different stages of disease progression. ResultsCR restored autophagy, as shown by decreased P62 punctae and quenched mTOR activation specifically in mutant uromodulin expressing cells, it recovered expression of key ER-phagy receptor genes, with a concomitant, striking reduction of mutant uromodulin ER retention. In pre-symptomatic TgUmodC147W mice, CR alleviates epithelial cell stress. This, likely along with a direct anti-inflammatory effect of CR, prevents inflammation and progressive decline of kidney function. At this early disease stage, CR ameliorates the already established kidney damage and reduces fibrosis, suggesting reversal of ADTKD phenotype. CR was also effective in significantly delaying disease progression in TgUmodC147W mice with advanced disease and already compromised kidney function. ConclusionOur findings establish the proof-of-principle that counteracting the primary effect of UMOD mutations by stimulating autophagy and quenching inflammation prevents disease onset and progression. This study uncovers the potential of CR as a valuable therapeutic option in the context of ADTKD-UMOD, and possibly other proteinopathies. Key pointsO_LICalorie restriction (CR) stimulates autophagy to degrade mutant uromodulin leading to amelioration of cell stress and tubular damage. C_LIO_LIAt early disease stage CR reverts ADTKD-UMOD phenotype, by preventing inflammation and progressive decline of kidney function and rescuing fibrosis. C_LIO_LIAt advanced disease stage, CR significantly delays disease progression and worsening of kidney function. C_LI