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.