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

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.

Genetically Predicted Circulating Copper and Risk of Chronic Kidney Disease: A Mendelian Randomization Study

“…Circulating copper is somewhat genetically controlled [1], but humans are also exposed to copper through dietary intake and it reaches the kidney through blood circulation [18]. In the kidneys, copper catalyzes the production of highly reactive hydroxyl radical species, so this oxidative stress can cause proximal tube necrosis [5,18]. Previously, through observational epidemiological studies, it has been reported that higher copper intake has been associated with abnormal eGFR [16] and end stage CKD [19].…”

“…Excessive dietary copper intake can lead to deposition of copper in the kidney and cause nephrotoxicity characterized by proximal tube necrosis that results through oxidative stress, cellular injury, and leads to a decline in kidney function [4]. However, the interplay between copper and kidney disease is bi-directional as imbalances in the homeostasis of circulating copper levels may also occur as a result of impaired renal excretion and changes in protein metabolism in patients with chronic kidney disease (CKD) [5]. In fact, the regulation of copper levels in CKD patients is important to prevent complications.…”

Selective depletion of hepatic stellate cells‐specific LOXL1 alleviates liver fibrosis

“…22,38 In addition to the liver, LOXL1 has also been shown to exert a fibrotic effect in lungs 39 and kidneys. 40 Indeed, the roles of LOX and LOXL2 in fibrosis have been well characterized, and their inhibition has yielded promising results in mouse experiments. 7,15,31,41 Therefore, the LOX family is a logical target for antifibrotic treatment.…”

Interstitial nephritis of unknown aetiology in captive slender‐horned gazelles (Gazella leptoceros)

“…Indeed, it has recently been demonstrated that intracellular copper accumulation is associated with kidney fibrosis and function. 30 The present case demonstrates that the search for a proper aetiology of interstitial nephritis remains challenging.…”

“…As copper ions play an important role in enzymatic processes in cells, changes in copper levels could have cellular effects. Indeed, it has recently been demonstrated that intracellular copper accumulation is associated with kidney fibrosis and function 30 …”