Abstract: SA-PO0623
Dietary Interventions Enhancing Autophagy Clear Uromodulin Aggregates and Slow Disease Progression in UMOD-Related Autosomal Dominant Tubulointerstitial Kidney Disease
Session Information
- Monogenic Kidney Diseases: Tubular and Other
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Mariniello, Marta, Universitat Zurich Physiologisches Institut, Zürich, ZH, Switzerland
- Costa, Inês, Universite catholique de Louvain Institut de Recherche Experimentale et Clinique, Brussels, Belgium
- Guo, Qin, Universitat Zurich Physiologisches Institut, Zürich, ZH, Switzerland
- Cratere, Mariapia Giuditta, IRCCS Ospedale San Raffaele, Milan, Lombardy, Italy
- Rampoldi, Luca, IRCCS Ospedale San Raffaele, Milan, Lombardy, Italy
- Olinger, Eric Gregory, Cliniques universitaires Saint-Luc, Brussels, Belgium
- Devuyst, Olivier, Universitat Zurich Physiologisches Institut, Zürich, ZH, Switzerland
Background
Missense mutations in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), a prevalent monogenic disorder which results in misfolding and aggregation of mutant uromodulin (UMOD) in the endoplasmic reticulum (ER) of thick ascending limb (TAL) cells, triggering ER stress and progressive kidney damage. While the underlying proteotoxic mechanisms are well characterized, no disease-modifying therapies currently exist. Pharmacologic or fasting-induced autophagy clears UMOD aggregates in vitro, suggesting that dietary interventions may modulate disease progression.
Methods
Nutritional strategies including progressive caloric restriction (CR), intermittent fasting (IF) and methionine restriction (MR) against control-fed diets were tested in two Umod knock-in (KI) mouse models with representative human mutations: p.Cys125Arg (mild, late-onset) and p.Arg186Ser (severe, early-onset). Heterozygous KI mice aged 5-8 weeks were exposed to dietary interventions for 4 to 16 weeks. Kidney function, histopathology, ER stress, bulk autophagy, reticulophagy, mTOR signaling and disease pathways were assessed. Studies in kidney cells stably expressing mutant UMOD explored how nutrient deprivation regulates autophagy and promotes aggregate clearance.
Results
All regimens induced modest (<15%), well-tolerated weight loss in the Umod KI mice, with strong inhibition of mTORC1 and activation of autophagy in the kidneys. These changes were reflected by a 50–60 % drop in immature UMOD and aggregates, lower ER stress levels, enhanced lysosomal flux, as well as suppression of tubular stress markers and matrix-remodeling pathways, alongside activation of ER-phagy in the treated kidneys. All diets significantly reduced leukocyte infiltration and/or fibrosis, and BUN levels. Mechanistically, nutrient starvation inhibited mTORC1, increased autophagosome formation and ER-phagy, accelerating clearance of ER-retained UMOD aggregates and reducing ER stress.
Conclusion
These findings indicate the therapeutic potential of autophagy-enhancing diets to restore proteostasis and preserve kidney function in mouse models of ADTKD-UMOD. These dietary approaches offer translatable strategies for patients with ADTKD-UMOD.