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Oxidized-LDL aggravates renal injury via tubular cuproptosis

Oxidized-LDL aggravates renal injury via tubular cuproptosis
Oxidized-LDL aggravates renal injury via tubular cuproptosis
Objective: the imbalance of copper homeostasis is closely related to development of kidney injury. We aimed to clarify the mechanism of oxidation of low-density lipoprotein (ox-LDL) aggravated renal injury via tubular copper overload and cuproptosis in lipid-related renal injury.

Methods: 313 patients with kidney disease (KD) confirmed by renal biopsy and 19 healthy participants were enrolled in this study. The copper levels in serum, urine and kidney tissue were assessed and the association between copper and renal function analyzed. We used ox-LDL and a high fat diet (HFD) to develop a pre-clinical renal injury model in HFD fed mice, and measured the levels of copper and cuproptosis biomarkers both in vivo and in vitro, respectively.

Results: compared to the healthy control group, KD patients showed higher serum and urinary copper levels. Estimated glomerular filtration rate was inversely correlated to serum copper, while 24-hour proteinuria was directly correlated to urinary copper levels. Abnormal deposition of copper salts were observed in kidney tissue of both ORN patients and HFD mice. In vivo and in vitro data showed that lipid may induce mitochondrial dysfunction and promote cuproptosis in tubular epithelial cells, which was related to changes in copper transporter protein ATP7B.

Conclusion: ox-LDL can promote copper overload in renal tubular cells by suppressing ATP7B, thereby inducing cuproptosis and promoting lipid-related kidney injury.
Copper overload, Cuproptosis, Lipid-related kidney injury, Renal tubule
0898-6568
Sun, Dan-Qin
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Zhong, Meng-Yang
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Zhang, Jia-Hui
d55fde18-9409-49d2-b87d-af978fb6aa28
Tang, Hong
28b0e69b-fdb5-4576-9e71-d9ac87bafe6c
Hu, Bin
160d7390-4ccf-463b-b023-6c180c66f57d
Shen, Jia-Qi
7c4c94ea-df5f-41e8-ab80-15cee56250ea
Yan, Feng
3a06a0cc-8fb2-4415-9f2f-f30621ec6a90
Xu, Xin-Yu
c458c942-e068-46f0-9c4f-b32f1b030a17
Chen, Ke
d1642b49-a561-4258-a402-5313ceffb14d
Targher, Giovanni
e6df3990-56c2-4edf-b437-7082d657a318
Byrne, Christopher D.
1370b997-cead-4229-83a7-53301ed2a43c
Zheng, Ming-Hua
986e37ab-28f9-4b26-afc5-9b2383df272a
Zhao, Jing
63b67512-a3f7-4a3e-9402-773bc0771f05
Wang, Rui-Fang
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Sun, Dan-Qin
efa9a8ed-ef94-4699-85a4-daba7465eff8
Zhong, Meng-Yang
f1f80fe3-5539-47c5-95e3-7afe4195a59b
Zhang, Jia-Hui
d55fde18-9409-49d2-b87d-af978fb6aa28
Tang, Hong
28b0e69b-fdb5-4576-9e71-d9ac87bafe6c
Hu, Bin
160d7390-4ccf-463b-b023-6c180c66f57d
Shen, Jia-Qi
7c4c94ea-df5f-41e8-ab80-15cee56250ea
Yan, Feng
3a06a0cc-8fb2-4415-9f2f-f30621ec6a90
Xu, Xin-Yu
c458c942-e068-46f0-9c4f-b32f1b030a17
Chen, Ke
d1642b49-a561-4258-a402-5313ceffb14d
Targher, Giovanni
e6df3990-56c2-4edf-b437-7082d657a318
Byrne, Christopher D.
1370b997-cead-4229-83a7-53301ed2a43c
Zheng, Ming-Hua
986e37ab-28f9-4b26-afc5-9b2383df272a
Zhao, Jing
63b67512-a3f7-4a3e-9402-773bc0771f05
Wang, Rui-Fang
26bae82b-0d09-4883-8fa5-cfd5a2c9d2f0

Sun, Dan-Qin, Zhong, Meng-Yang, Zhang, Jia-Hui, Tang, Hong, Hu, Bin, Shen, Jia-Qi, Yan, Feng, Xu, Xin-Yu, Chen, Ke, Targher, Giovanni, Byrne, Christopher D., Zheng, Ming-Hua, Zhao, Jing and Wang, Rui-Fang (2025) Oxidized-LDL aggravates renal injury via tubular cuproptosis. Cellular Signalling, 132, [111839]. (doi:10.1016/j.cellsig.2025.111839).

Record type: Article

Abstract

Objective: the imbalance of copper homeostasis is closely related to development of kidney injury. We aimed to clarify the mechanism of oxidation of low-density lipoprotein (ox-LDL) aggravated renal injury via tubular copper overload and cuproptosis in lipid-related renal injury.

Methods: 313 patients with kidney disease (KD) confirmed by renal biopsy and 19 healthy participants were enrolled in this study. The copper levels in serum, urine and kidney tissue were assessed and the association between copper and renal function analyzed. We used ox-LDL and a high fat diet (HFD) to develop a pre-clinical renal injury model in HFD fed mice, and measured the levels of copper and cuproptosis biomarkers both in vivo and in vitro, respectively.

Results: compared to the healthy control group, KD patients showed higher serum and urinary copper levels. Estimated glomerular filtration rate was inversely correlated to serum copper, while 24-hour proteinuria was directly correlated to urinary copper levels. Abnormal deposition of copper salts were observed in kidney tissue of both ORN patients and HFD mice. In vivo and in vitro data showed that lipid may induce mitochondrial dysfunction and promote cuproptosis in tubular epithelial cells, which was related to changes in copper transporter protein ATP7B.

Conclusion: ox-LDL can promote copper overload in renal tubular cells by suppressing ATP7B, thereby inducing cuproptosis and promoting lipid-related kidney injury.

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Accepted/In Press date: 26 April 2025
e-pub ahead of print date: 28 April 2025
Published date: 1 May 2025
Keywords: Copper overload, Cuproptosis, Lipid-related kidney injury, Renal tubule

Identifiers

Local EPrints ID: 502898
URI: http://eprints.soton.ac.uk/id/eprint/502898
ISSN: 0898-6568
PURE UUID: 531aefe0-1e19-4fdf-88db-e830e0811393
ORCID for Christopher D. Byrne: ORCID iD orcid.org/0000-0001-6322-7753

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Date deposited: 11 Jul 2025 16:37
Last modified: 11 Sep 2025 01:52

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Contributors

Author: Dan-Qin Sun
Author: Meng-Yang Zhong
Author: Jia-Hui Zhang
Author: Hong Tang
Author: Bin Hu
Author: Jia-Qi Shen
Author: Feng Yan
Author: Xin-Yu Xu
Author: Ke Chen
Author: Giovanni Targher
Author: Ming-Hua Zheng
Author: Jing Zhao
Author: Rui-Fang Wang

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