Xanthine Oxidoreductase Depletion Induces Renal Interstitial Fibrosis Through Aberrant Lipid and Purine Accumulation in Renal Tubules

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 54; no. 4; pp. 868 - 876
• Main Authors: Ohtsubo, Toshio, Matsumura, Kiyoshi, Sakagami, Kanae, Fujii, Koji, Tsuruya, Kazuhiko, Noguchi, Hideko, Rovira, Ilsa I, Finkel, Toren, Iida, Mitsuo
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.10.2009; Lippincott Williams & Wilkins
• Subjects: Adipogenesis - genetics; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Disease Models, Animal; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Fibrosis; Fundamental and applied biological sciences. Psychology; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) - metabolism; Hypoxanthine - metabolism; Kidney Tubules - metabolism; Kidney Tubules - pathology; Lipid Metabolism - physiology; Lipogenesis - genetics; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephritis, Interstitial - metabolism; Nephritis, Interstitial - pathology; Nephritis, Interstitial - physiopathology; Oxidative Stress - physiology; Purines - metabolism; Triglycerides - metabolism; Vertebrates: urinary system; Xanthine - metabolism; Xanthine Dehydrogenase - genetics; Xanthine Dehydrogenase - metabolism; Hypertension; Oxidative stress; Purine derivatives; xanthine oxidoreductase; Enzyme; Cardiovascular disease; Uric acid; Xanthine; Epithelium; lipid; renal interstitial fibrosis; Renal tubule; epithelial mesenchymal transition; Depletion; Fibrosis; Transition; Purine; Oxidoreductases
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.109.135152

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.