Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules.
Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules.
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DOI：
10.1161/hypertensionaha.109.135152
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发表时间：
2009-10
期刊：
影响因子：
--
通讯作者：
Iida M
中科院分区：
文献类型：
--
作者：
Ohtsubo T;Matsumura K;Sakagami K;Fujii K;Tsuruya K;Noguchi H;Rovira II;Finkel T;Iida M
黄嘌呤氧化还原酶（XOR）是一种负责嘌呤降解、活性氧（ROS）产生和脂肪生成的酶。XOR基因破坏（XOR−/−）小鼠在几个月内表现出肾衰竭和早期死亡。本研究的目的是阐明XOR - / -小鼠肾脏损伤的机制，并确定XOR在肾脏中的生理作用。组织学分析显示，XOR−/−小鼠肾小管损伤伴随着晶体和富脂物质的沉积。XOR−/−小鼠肾匀浆中甘油三酯含量显著增加。在XOR+/+和XOR - / -小鼠中，脂肪生成相关基因表达水平相当，而在XOR - / -小鼠中，脂肪生成相关基因表达显著升高。XOR−/−小鼠尿中黄嘌呤和次黄嘌呤的排泄量明显升高。免疫组织化学分析、Western blotting和实时RT-PCR显示，XOR−/−小鼠的纤维化、炎症、缺血和氧化应激等各种标志物均升高。最后，我们证明了XOR - / -小鼠的原代肾上皮细胞更容易转化为肌成纤维细胞，这是上皮间充质转化增加的标志。这些结果表明，XOR基因破坏诱导了尿酸的消耗和富甘油三酯物质、黄嘌呤和次黄嘌呤在肾小管中的积累。我们认为，这些变化有助于形成以炎症、组织缺氧和ROS产生为特征的复杂细胞环境，最终通过肾间质纤维化增加导致肾功能衰竭。
Xanthine oxidoreductase (XOR) is an enzyme responsible for purine degradation, reactive oxygen species (ROS) 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, while 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 these changes contribute to a complex cellular milieu characterized by inflammation, tissue hypoxia and ROS production ultimately resulting in renal failure through increased renal interstitial fibrosis.