title: Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules.
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.
authors: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, Japan. tohtsubo@intmed2.med.kyushu-u.ac.jp
authors: Toshio
authors: T
authors: Ohtsubo
authors: Kiyoshi
authors: K
authors: Matsumura
authors: Kanae
authors: K
authors: Sakagami
authors: Koji
authors: K
authors: Fujii
authors: Kazuhiko
authors: K
authors: Tsuruya
authors: Hideko
authors: H
authors: Noguchi
authors: Ilsa I
authors: II
authors: Rovira
authors: Toren
authors: T
authors: Finkel
authors: Mitsuo
authors: M
authors: Iida
mesh_terms: D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005355:Fibrosis; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism; D019271:Hypoxanthine / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology*; D050356:Lipid Metabolism / Q000502:physiology; D050155:Lipogenesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009395:Nephritis, Interstitial / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology; D011687:Purines / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism*; D019820:Xanthine / Q000378:metabolism; D014968:Xanthine Dehydrogenase / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011687:Purines; D014280:Triglycerides; D019820:Xanthine; D019271:Hypoxanthine; D014968:Xanthine Dehydrogenase; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); C030985:purine