Elevated intracellular copper contributes a unique role to kidney fibrosis by lysyl oxidase mediated matrix crosslinking
Elevated intracellular copper contributes a unique role to kidney fibrosis by lysyl oxidase mediated matrix crosslinking
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细胞内铜升高通过赖氨酰氧化酶介导的基质交联对肾纤维化发挥独特作用
DOI：
10.1038/s41419-020-2404-5
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发表时间：
2020-03-31
影响因子：
9
通讯作者：
Yu, Chen
中科院分区：
文献类型：
--
作者：
Niu, Yang-yang;Zhang, Ying-ying;Yu, Chen
铜离子在哺乳动物细胞中发挥着各种作用，可能是由于它们参与了不同的酶反应。有研究表明，血清铜与肝、肺等器官的纤维化有关。然而，其机制尚不清楚。在这里，我们探讨了铜在肾纤维化发展中的作用和可能的潜在机制。我们发现，铜转运蛋白1（CTR 1）的表达增加，在两个纤维化模型和肾纤维化患者的肾组织。在转化生长因子β（TGF-β）处理的肾小管上皮细胞和成纤维细胞中也发现了类似的结果。CTR 1的上调需要Smads依赖的TGF-β信号通路，并且使用染色质免疫沉淀法在肾成纤维细胞中Smad 3直接与CTR 1的启动子结合。升高的CTR 1诱导铜细胞内流增加。升高的细胞内铜离子激活赖氨酰氧化酶（LOX），以增强胶原和弹性蛋白的交联，从而促进肾纤维化。在单侧输尿管梗阻诱导的肾纤维化模型和TGF-β刺激的肾成纤维细胞中，通过敲除CTR 1减少细胞内铜积聚可改善肾纤维化。用铜螯合剂四硫代钼酸盐（TM）治疗也减轻了体内和体外肾纤维化。总之，细胞内铜蓄积通过激活LOX介导的胶原和弹性蛋白交联在肾纤维化中发挥独特作用。抑制细胞内铜超载可能是减轻肾纤维化的潜在途径。
Copper ions play various roles in mammalian cells, presumably due to their involvement in different enzymatic reactions. Some studies indicated that serum copper correlates with fibrosis in organs, such as liver and lung. However, the mechanism is unknown. Here, we explored the role of copper in kidney fibrosis development and possible underlying mechanisms. We found that copper transporter 1 (CTR1) expression was increased in the kidney tissues in two fibrosis models and in patients with kidney fibrosis. Similar results were also found in renal tubular epithelial cells and fibroblast cells treated with transforming growth factor beta (TGF-β). Mechanistically, the upregulation of CTR1 required Smads-dependent TGF-β signaling pathway and Smad3 directly binded to the promoter of CTR1 in renal fibroblast cells using chromatin immunoprecipitation. Elevated CTR1 induced increase of copper intracellular influx. The elevated intracellular copper ions activated lysyl oxidase (LOX) to enhance the crosslinking of collagen and elastin, which then promoted kidney fibrosis. Reducing intracellular copper accumulation by knocking down CTR1 ameliorated kidney fibrosis in unilateral ureteral obstruction induced renal fibrosis model and renal fibroblast cells stimulated by TGF-β. Treatment with copper chelator tetrathiomolybdate (TM) also alleviated renal fibrosis in vivo and in vitro. In conclusion, intracellular copper accumulation plays a unique role to kidney fibrosis by activating LOX mediated collagen and elastin crosslinking. Inhibition of intracellular copper overload may be a potential portal to alleviate kidney fibrosis.