| First Author | Ohtsubo T | Year | 2009 |
| Journal | Hypertension | Volume | 54 |
| Issue | 4 | Pages | 868-76 |
| PubMed ID | 19667249 | Mgi Jnum | J:166326 |
| Mgi Id | MGI:4844048 | Doi | 10.1161/HYPERTENSIONAHA.109.135152 |
| Citation | Ohtsubo T, et al. (2009) Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules. Hypertension 54(4):868-76 |
| abstractText | 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. |
