Kidney Week

Abstract: SA-PO0621

Calorie Restriction Promotes Degradation of Mutant Uromodulin and Ameliorates Inflammation and Fibrosis 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

• Cratere, Mariapia Giuditta, IRCCS Ospedale San Raffaele, Milan, Lombardy, Italy

Mariapia Giuditta Cratere, PhD

• Mariniello, Marta, Institute of Physiology, University of Zurich, Zurich, Switzerland

Marta Mariniello, PhD

• Perrone, Benedetta, IRCCS Ospedale San Raffaele, Milan, Lombardy, Italy

Benedetta Perrone, MSc

• Canciani, Barbara, IRCCS Ospedale Galeazzi-Sant’Ambrogio, Milan, Italy

Barbara Canciani, PhD

• Schaeffer, Celine, IRCCS Ospedale San Raffaele, Milan, Lombardy, Italy

Celine Schaeffer, PhD

• Devuyst, Olivier, Institute of Physiology, University of Zurich, Zurich, Switzerland

Olivier Devuyst, MD, PhD

• Rampoldi, Luca, IRCCS Ospedale San Raffaele, Milan, Lombardy, Italy

Luca Rampoldi, PhD

Background

Mutations in UMOD, encoding uromodulin, lead to Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD-UMOD), a genetic cause of end-stage kidney disease characterized by interstitial inflammation and fibrosis. UMOD mutations have a common gain-of-toxic-function effect, causing mutant uromodulin retention and aggregation in the endoplasmic reticulum (ER). Other phenotypes of cells expressing mutant uromodulin are ER stress, mitochondrial dysfunction, altered protein homeostasis and impaired autophagy. Calorie restriction (CR) was shown to be beneficial in different diseases characterized by accumulation of pathogenic protein and inflammation, by acting on several mechanisms, including autophagy induction and suppression of inflammation. Given the relevance of these features in the disease, we investigated the effect CR in ADTKD-UMOD.

Methods

Transgenic mice expressing C147W mutant uromodulin (Tg^UmodC147W) were subjected to a moderate (30%) CR regimen for 4, 15 or 24 weeks, starting at different stages of disease progression. Knock-in mice expressing R186S mutant uromodulin (Umod^R186S/+) were subjected to 30% CR for 4 weeks.

Results

CR restored autophagy, as shown by decreased p62 punctae and quenched mTOR hyperactivity specifically in mutant uromodulin expressing cells, it recovered expression of key ER-phagy receptor genes, and it led to a striking reduction of mutant uromodulin ER retention. In pre-symptomatic Tg^UmodC147W mice, CR alleviates epithelial cell stress and 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 ADTKD reversal. Importantly, CR was also effective in blocking disease progression in Tg^UmodC147W mice with already compromised kidney function. All main beneficial effects of CR on ADTKD-UMOD phenotype were confirmed in the Umod^R186S/+ mouse model.

Conclusion

These findings establish the proof-of-principle that counteracting the primary effect of UMOD mutations can prevent ADTKD-UMOD onset and progression and uncover the potential of CR as a valuable therapeutic option.

Funding

• Private Foundation Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.202518nn4ad4