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

Calorie restriction restored autophagy, as shown by decreased P62 punctae and quenched 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 pre-symptomatic TgUmodC147W 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 TgUmodC147W 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.

Complete data files relative to the manuscript "Cratere MG, Perrone B, Canciani B, Schaeffer C, Rampoldi L. Calorie Restriction Leads to Degradation of Mutant Uromodulin and Ameliorates Inflammation and Fibrosis in UMOD-Related Kidney Disease. J Am Soc Nephrol. 2026 Feb 3. doi: 10.1681/ASN.0000001032. Epub ahead of print.

PMID: 41632531".