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Abstract: FR-PO601

A Canine Model Implicates Uromodulin Peptides in Calcium Oxalate Urinary Stone Risk

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Furrow, Eva, University of Minnesota Twin Cities College of Veterinary Medicine, Saint Paul, Minnesota, United States
  • Rampoldi, Luca, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
  • Jovine, Luca, Karolinska Institutet, Stockholm, Stockholm, Sweden
  • Wesson, Jeffrey, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Jayachandran, Muthuvel, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, United States
  • Lieske, John C., Mayo Clinic College of Medicine and Science, Rochester, Minnesota, United States
  • Romero, Michael F., Mayo Clinic College of Medicine and Science, Rochester, Minnesota, United States
  • Lulich, Jody Pierre, University of Minnesota Twin Cities College of Veterinary Medicine, Saint Paul, Minnesota, United States
Background

Dogs offer a spontaneous model of calcium oxalate (CaOx) urinary stone formation. Our previous research identified a pathogenic variant (PV) in the canine uromodulin gene (UMOD) that is associated with a dramatic risk for CaOx stones. This stone-risk PV resides in the external hydrophobic patch (EHP) of uromodulin, which is cleaved from the mature protein before secretion into tubular fluid. In this study, we characterized urinary excretion of EHP-containing peptides from CaOx stone former (SF) dogs with and without the UMOD PV.

Methods

Urinary uromodulin peptides were measured in urine samples from SFs with (n=4) and without (n=4) the UMOD PV plus healthy control dogs (n=7) and normalized to urinary creatinine. Dogs with kidney disease were excluded. Uromodulin peptide abundances were summed for comparisons of total excretion. For individual peptides, abundance was calculated relative to the sum of all uromodulin peptides to obtain a percentage. Cleavage patterns were compared between groups.

Results

Total uromodulin peptide abundance was reduced in SF dogs with the UMOD PV. Urine from PV SF dogs lacked a peptide cleavage site, resulting in longer peptides compared to healthy controls. Total uromodulin peptide abundance did not differ between non-PV SF and healthy dogs. However, non-PV SF dogs had decreased abundance of specific EHP-containing peptides that was intermediate between healthy and PV SF dogs (Figure 1).

Conclusion

Reduced urinary excretion of specific uromodulin peptides in CaOx SF dogs with and without the UMOD PV implicates these peptides in stone risk. Previous research has demonstrated bioactivity of uromodulin peptides. The peptides that are decreased in the urine of SF dogs may have a protective effect against stone formation.

Funding

  • Other NIH Support