Abstract—Xanthine oxidoreductase (XOR) is an enzyme responsible for purine degradation, reactive oxygen species production, and adipogenesis. XOR gene-disrupted (XOR^-/-) mice demonstrate renal failure and early death within several months. The aim of this study was to elucidate the mechanism of renal damage in XOR^-/- mice and to determine the physiological role of XOR in the kidney. Histological analysis revealed that renal tubular damage in XOR^-/- mice was accompanied by deposition of crystals and lipid-rich substances. Triglyceride content in renal homogenates was significantly increased in XOR^-/- mice. The level of lipogenesis-related gene expression was comparable in XOR^+/+ and XOR^-/- mice, whereas the expression of adipogenesis-related gene expression was significantly elevated in XOR^-/- mice. Urinary excretions of xanthine and hypoxanthine were markedly elevated in XOR^-/- mice. Immunohistochemical analysis, Western blotting, and real time RT-PCR revealed that various markers of fibrosis, inflammation, ischemia, and oxidative stress were increased in XOR^-/- mice. Finally, we demonstrate that primary renal epithelial cells from XOR^-/- mice are more readily transformed to myofibroblasts, which is a marker of increased epithelial mesenchymal transition. These results suggest that XOR gene disruption induced the depletion of uric acid and the accumulation of triglyceride-rich substances, xanthine, and hypoxanthine in the renal tubules. We believe that these changes contribute to a complex cellular milieu characterized by inflammation, tissue hypoxia, and reactive oxygen species production, ultimately resulting in renal failure through increased renal interstitial fibrosis.