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To date, most studies on organ fibrosis have focused on the accumulation of ECM however, studies targeting ECM crosslinking for fibrosis are rare. Under pathological conditions, overproduction ECM and overactivated ECM crosslinking contributes to organ fibrosis 10. Therefore, the level of intracellular copper determines the activity of LOX. LOX becomes active when combined with copper in the Golgi and is then secreted extracellularly to crosslink elastin and collagen 8, 9. Lysyl oxidase (LOX), a copper-dependent enzyme, is the most important enzyme for ECM crosslinking. This process is called ECM crosslinking and is critical for the maintenance of a stable matrix 6, 7. Under physiological conditions, most of these molecules are assembled into microfibrils, which are arranged in parallel in quarter-staggered arrays with overlap and gap regions, assembled into three-dimensional fibrils, and finally, the elastin and collagen molecules become insoluble. The core foundation of fibrosis is the ECM, which includes elastin, collagen, fibronectin, and oxytalan fibers. However, there have been no reports of association of copper with fibrosis in the kidney, and the underlying mechanism involving the role of copper in organ fibrosis is unknown. Recently, some studies have shown that copper accumulation is associated with fibrosis in various tissues such as in human liver 3, oral submucous tissue in humans 4 and lung fibrosis in rats 5. Because there are currently no specific treatments for renal fibrosis, a deeper understanding of the molecular and cellular basis of renal fibrosis will be beneficial to the development of effective strategies that diminish or even reverse kidney fibrosis in CKD.Ĭopper is one of the most important trace elements in the human body, as it is a cofactor or structural component for many enzymes that are required for cellular physiology 1, 2. Kidney fibrosis is characterized by excess accumulation of extracellular matrix (ECM) substances in kidney. Kidney fibrosis is the principal process and the final common pathway underlying the progression of all chronic kidney disease (CKD) to end stage of kidney disease (ESKD). Inhibition of intracellular copper overload may be a potential portal to alleviate kidney fibrosis. In conclusion, intracellular copper accumulation plays a unique role to kidney fibrosis by activating LOX mediated collagen and elastin crosslinking. Treatment with copper chelator tetrathiomolybdate (TM) also alleviated renal fibrosis in vivo and in vitro. 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.
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The elevated intracellular copper ions activated lysyl oxidase (LOX) to enhance the crosslinking of collagen and elastin, which then promoted kidney fibrosis. Elevated CTR1 induced increase of copper intracellular influx. 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. Similar results were also found in renal tubular epithelial cells and fibroblast cells treated with transforming growth factor beta (TGF-β). We found that copper transporter 1 (CTR1) expression was increased in the kidney tissues in two fibrosis models and in patients with kidney fibrosis. Here, we explored the role of copper in kidney fibrosis development and possible underlying mechanisms. Some studies indicated that serum copper correlates with fibrosis in organs, such as liver and lung. Copper ions play various roles in mammalian cells, presumably due to their involvement in different enzymatic reactions.