Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules. Export

@article{citeulike:6031339, 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.}, author = {Ohtsubo, Toshio and Matsumura, Kiyoshi and Sakagami, Kanae and Fujii, Koji and Tsuruya, Kazuhiko and Noguchi, Hideko and Rovira, Ilsa I. and Finkel, Toren and Iida, Mitsuo}, citeulike-article-id = {6031339}, citeulike-linkout-0 = {http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.135152}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19667249}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19667249}, doi = {10.1161/HYPERTENSIONAHA.109.135152}, issn = {1524-4563}, journal = {Hypertension}, keywords = {fibrosis, lipid, pt, ros}, month = {October}, number = {4}, pages = {868--876}, posted-at = {2009-10-29 06:10:47}, priority = {2}, title = {Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules.}, url = {http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.135152}, volume = {54}, year = {2009} }

TY - JOUR ID - citeulike:6031339 L3 - citeulike-article-id:6031339 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. 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. IS - 4 JF - Hypertension SN - 1524-4563 EP - 876 TI - Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules. VL - 54 SP - 868 KW - fibrosis KW - lipid KW - pt KW - ros AU - Ohtsubo, Toshio AU - Matsumura, Kiyoshi AU - Sakagami, Kanae AU - Fujii, Koji AU - Tsuruya, Kazuhiko AU - Noguchi, Hideko AU - Rovira, Ilsa AU - Finkel, Toren AU - Iida, Mitsuo PY - 2009/10// UR - http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.135152 ER -