Vitamin D3 up-regulated protein-1 regulates collagen expression in mesangial cells
Vitamin D3 up-regulated protein-1 regulates collagen expression in mesangial cells
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DOI：
10.1046/j.1523-1755.2003.00263.x
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发表时间：
2003-11-01
影响因子：
19.6
通讯作者：
Kotani, H
中科院分区：
文献类型：
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作者：
Kobayashi, T;Uehara, S;Kotani, H
背景资料。高血糖是肾病发病机制中已知的危险因素，而活性氧自由基(ROS)增加导致的胶原堆积被认为是高糖介导疾病的原因之一。然而，将葡萄糖刺激、氧化应激和胶原诱导联系起来的分子机制尚不清楚。我们利用DNA微阵列技术检测了高糖刺激后培养的人肾小球系膜细胞基因表达模式的整体变化。采用定量逆转录聚合酶链式反应(RT-PCR)方法，研究了维生素D-3上调蛋白-1(VDUP-1)在人肾小球系膜细胞、小鼠肾小球系膜细胞系和糖尿病小鼠肾脏中的表达。用截短的VDUP-1蛋白检测VDUP-1对系膜细胞胶原生物合成的影响。DNA芯片分析表明，高浓度葡萄糖作用后，硫氧还蛋白抑制物VDUP-1的表达迅速而稳定。VDUP-1基因在培养的肾小球系膜细胞中过表达导致IV型胶原α1链(COL4A1)mRNA的诱导和IV型胶原蛋白的积聚。然而，COL4A1的诱导表达被VDUP-1的缺失突变体所取消，该突变体失去了硫氧还蛋白相互作用结构域。此外，链脲佐菌素诱导的糖尿病小鼠VDUP-1和COL4A1也有高表达。VDUP-1介导肾小球系膜细胞胶原沉积，可作为糖尿病等慢性高血糖所致糖尿病肾病纤维化的分子介质/标记物。
Background. Hyperglycemia is a known risk factor in the pathogenesis of nephropathy, and collagen accumulation due to an increase reactive oxygen species (ROS) has been suspected to be one of the reasons for high glucose-mediated diseases. However, molecular mechanisms that connect glucose stimulation, oxidative stress, and collagen induction are unknown.Methods. We examined global changes in gene expression patterns following high glucose stimulation by using DNA microarray technology in cultured human mesangial cells. The expression of vitamin D-3 up-regulated protein-1 (VDUP-1), our candidate for the molecular mediator, was evaluated in the human mesangial cells, mouse mesangial cell line, and kidneys of diabetic mice by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Truncated VDUP-1 proteins were used to test the effects of VDUP-1 on the biosynthesis of collagen in mesangial cells.Results. Expression of VDUP-1, which was reported as an inhibitor of thioredoxin, was induced rapidly and constantly after exposure to high concentrations of glucose upon analysis with DNA microarray. Overexpression of VDUP-1 gene in cultured mesangial cells resulted in type IV collagen alpha1 chain (COL4A1) mRNA induction and accumulation of type IV collagen protein. However, induction of COL4A1 expression was abolished with a deletion mutant of VDUP-1, which lost thioredoxin-interacting domain. Also, streptozotocin-induced diabetic mice were shown to overexpress VDUP-1 as well as COL4A1.Conclusion. VDUP-1 mediates collagen accumulation in mesangial cells and could be the molecular mediator/marker for fibrosis in diabetic nephropathy caused by chronic hyperglycemia such as diabetes.