Calorie Restriction Leads to Degradation of Mutant Uromodulin and Ameliorates Inflammation and Fibrosis in UMOD -Related Kidney Disease.

Abstract

Calorie restriction stimulated autophagy and degradation of mutant uromodulin, leading to amelioration of cell stress and tubular damage. At early disease stage, calorie restriction largely reverted autosomal dominant tubulointerstitial kidney disease (ADTKD)- UMOD phenotype, preventing inflammation, fibrosis, and kidney function decline. At advanced disease stage, calorie restriction significantly delayed disease progression and worsening of kidney function. Mutations 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 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 calorie restriction on disease onset and progression. Transgenic mice expressing C147W uromodulin (Tg Umod C147W ) were subjected to a moderate (30%) calorie restriction regimen for 15 or 24 weeks, starting at different stages of disease progression. Calorie restriction restored autophagy, as shown by decreased P62 punctae and quenched mammalian target of rapamycin (mTOR) activation specifically in mutant uromodulin-expressing cells, and it recovered expression of key ER-phagy receptor genes, with a concomitant, striking reduction of mutant uromodulin ER retention. In presymptomatic Tg Umod C147W mice, calorie restriction alleviated epithelial cell stress. This, likely along with a direct anti-inflammatory effect of calorie restriction, prevented inflammation and progressive decline of kidney function. At this early disease stage, calorie restriction ameliorated the already established kidney damage and reduced fibrosis, suggesting reversal of ADTKD phenotype. Calorie restriction was also effective in significantly delaying disease progression in Tg Umod C147W mice with advanced disease and already compromised kidney function. Calorie restriction enhanced autophagy and uromodulin degradation, counteracting the primary effect of UMOD mutations, and significantly ameliorated kidney disease onset and progression.