TY - JOUR
T1 - Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules
AU - Ohtsubo, Toshio
AU - Matsumura, Kiyoshi
AU - Sakagami, Kanae
AU - Fujii, Koji
AU - Tsuruya, Kazuhiko
AU - Noguchi, Hideko
AU - Rovira, Ilsa I.
AU - Finkel, Toren
AU - Iida, Mitsuo
PY - 2009/10
Y1 - 2009/10
N2 - 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. mmunohistochemical 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.
AB - 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. mmunohistochemical 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.
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U2 - 10.1161/HYPERTENSIONAHA.109.135152
DO - 10.1161/HYPERTENSIONAHA.109.135152
M3 - Article
C2 - 19667249
AN - SCOPUS:70349672857
VL - 54
SP - 868
EP - 876
JO - Hypertension
JF - Hypertension
SN - 0194-911X
IS - 4
ER -