Kidney stones are a painful and common health problem, occurring in 8-12% of the population. Most kidney stones are composed of calcium oxalate (CaOx). Current therapies to prevent CaOx kidney stones have low efficacy, and recurrence rates are high. Pet dogs are an exceptional model of kidney stone disease. They naturally form CaOx kidney stones and share environmental and metabolic risk factors with humans. Using this natural model, we discovered a genetic variant in the uromodulin gene that has a profound effect on stone risk. Uromodulin (aka Tamm-Horsfall protein) is the most abundant protein secreted in urine and has long been linked to human kidney stone disease. The canine stone-risk variant is located within a sequence of uromodulin that is necessary for polymerization and excretion of small bioactive peptides. Our preliminary work demonstrated that both polymerization and peptides are disturbed in dogs with the variant, implicating these uromodulin features in stone pathogenesis. Our overarching objective is to identify the renal cellular and molecular mechanisms by which uromodulin polymerization status and peptides impact stone formation. The proposed study will test the hypothesis that defects in uromodulin polymerization status and peptides cause alterations in renal solute transporters/channels (Aim 1) and inflammatory cytokines involved in stone formation (Aim 2). The results of this work will identify disturbances in renal solute transport and inflammatory molecules that occur with abnormal uromodulin polymerization and peptide excretion. This will provide important insight into how uromodulin features affect its functions in the kidney. Uromodulin polymerization and peptide excretion can be modified with diet or drugs. Thus, the proposed research will lay the groundwork for future development of therapies to mitigate risk for CaOx kidney stone recurrence in humans.