Loss of the Kidney Urate Transporter, Urat1, Leads to Disrupted Redox Homeostasis in Mice.
Loss of the Kidney Urate Transporter, Urat1, Leads to Disrupted Redox Homeostasis in Mice.
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DOI：
10.3390/antiox12030780
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发表时间：
2023-03-22
期刊：
影响因子：
7
通讯作者：
Nigam, Sanjay K.
中科院分区：
文献类型：
--
作者：
Jamshidi, Neema;Nigam, Kabir B.;Nigam, Sanjay K.
关键词：
高尿酸与痛风、高血压、代谢综合征、心血管疾病和肾脏疾病有关。URAT1(SLC22A12)最初在小鼠中被发现为RST，与其他密切相关的肾脏尿酸转运蛋白如OAT1(SLC22A6，NKT)和OAT3(SLC22A8)相比，通常被认为是一种非常有选择性的尿酸转运蛋白。虽然URAT1在调节人类尿酸中的作用已被证实，但在最近的研究中，该基因与果蝇的氧化还原调节以及肾癌的进展有关。我们现在已经在Urat1基因敲除小鼠中鉴定出20多种代谢物，它们通常不同于Oat1和OAT3基因敲除小鼠中积累的代谢物，通过化学信息学和机器学习分析揭示了不同的分子特性。这些代谢物涉及细胞代谢的看似完全不同的方面，包括嘧啶、脂肪酸和氨基酸代谢。然而，通过使用人类代谢重建对转录和代谢数据进行整合系统的代谢分析以建立代谢基因组规模模型(GEMS)，细胞对URAT1/RST缺失的反应揭示了与通过维生素C代谢和辅因子充电反应处理和维持氧化还原状态平衡有关的代偿过程。这些观察结果与人们越来越多地认识到尿酸的抗氧化特性的作用是一致的。总体而言，这些结果强调了Urat1/RST作为与维持氧化还原动态平衡密切相关的转运体的作用，并暗示了阻断其功能的药物的代谢副作用。
High uric acid is associated with gout, hypertension, metabolic syndrome, cardiovascular disease, and kidney disease. URAT1 (SLC22A12), originally discovered in mice as Rst, is generally considered a very selective uric acid transporter compared to other closely-related kidney uric acid transporters such as OAT1 (SLC22A6, NKT) and OAT3 (SLC22A8). While the role of URAT1 in regulating human uric acid is well-established, in recent studies the gene has been linked to redox regulation in flies as well as progression of renal cell carcinoma. We have now identified over twenty metabolites in the Urat1 knockout that are generally distinct from metabolites accumulating in the Oat1 and Oat3 knockout mice, with distinct molecular properties as revealed by chemoinformatics and machine learning analysis. These metabolites are involved in seemingly disparate aspects of cellular metabolism, including pyrimidine, fatty acid, and amino acid metabolism. However, through integrative systems metabolic analysis of the transcriptomic and metabolomic data using a human metabolic reconstruction to build metabolic genome-scale models (GEMs), the cellular response to loss of Urat1/Rst revealed compensatory processes related to reactive oxygen species handling and maintaining redox state balances via Vitamin C metabolism and cofactor charging reactions. These observations are consistent with the increasingly appreciated role of the antioxidant properties of uric acid. Collectively, the results highlight the role of Urat1/Rst as a transporter strongly tied to maintaining redox homeostasis, with implications for metabolic side effects from drugs that block its function.
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影响因子：
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作者：
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作者：
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