Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules.
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.
Ohtsubo
Toshio
T
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
Matsumura
Kiyoshi
K
Sakagami
Kanae
K
Fujii
Koji
K
Tsuruya
Kazuhiko
K
Noguchi
Hideko
H
Rovira
Ilsa I
II
Finkel
Toren
T
Iida
Mitsuo
M
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*
D011687:Purines; D014280:Triglycerides; D019820:Xanthine; D019271:Hypoxanthine; D014968:Xanthine Dehydrogenase; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); C030985:purine