Elevated intracellular copper contributes a unique role to kidney fibrosis by lysyl oxidase mediated matrix crosslinking

Yang-Yang Niu,Chen Yu,Ye Song,Bengt Lindholm,Ying-Ying Zhang,Xiao-Qin Zhang,Sai-Ya Zhu,Xian Jin,Zhi Zhu,Xi Liu

doi:10.1038/s41419-020-2404-5

Abstract

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.

Highlights

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)
The copper level is elevated in kidney fibrotic tissue We assessed the levels of some metal ions in the kidney tissue of the uIRIx induced renal fibrosis model and found that only copper level was significantly increased, but not other metal ions, such as zinc, magnesium, manganese, iron, chrome, and calcium, determined by inductively coupled plasma-mass spectrometry (ICP-MS), compared to that in the sham mice (Fig. 1a)
Several previous studies have reported that increased circulating levels of copper associate with fibrosis and organ damage in animals[3,4,5] and humans[18,19]; the mechanism by which an elevated serum copper concentration leading to intracellular copper overload could induce organ fibrosis was not investigated in these studies

Summary

Introduction

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). Kidney fibrosis is characterized by excess accumulation of extracellular matrix (ECM) substances in Copper 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]. Official journal of the Cell Death Differentiation Association. Most of these molecules are assembled into microfibrils, which are arranged in parallel in quarter-staggered arrays with overlap and gap regions, assembled into threedimensional fibrils, and the elastin and collagen molecules become insoluble. This process is called ECM crosslinking and is critical for the maintenance of a stable matrix[6,7]

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