Steroidogenic factor 1 promotes cuproptosis in renal tubular epithelial cells during acute kidney injury

Abstract

Abstract Programmed cell death of renal tubular epithelial cells (RTECs) is the main pathophysiological mechanism of acute kidney injury (AKI). Copper-induced death is a newly discovered form of programmed cell death, mainly attributed to fatty acylation in the TCA cycle, which leads to mitochondrial stress and cell death. However, the role of copper-induced death in the occurrence and development of AKI remains unclear. In this study, we first identified that the expression of ferredoxin 1 (FDX1), a key gene for copper-induced death, was significantly increased in the renal tissues of patients with AKI. The expression of copper-induced death-related genes and copper transporter 1 (CTR1) was significantly increased in various animal models of AKI. Compared with the control group, in the hypoxia-reoxygenation (H/R), lipopolysaccharide, and cisplatin injury groups, the concentration of copper ions increased in the NRK-52E cells, and the expression of FDX1 and CTR1 proteins increased significantly. After the NRK-52E cells were stimulated by copper (Cu2+), elesclomol (ES), and Cu2+ + ES, the expression of CTR1 and FDX1 increased in the Cu2+ + ES group, and that of lactate dehydrogenase increased significantly. In addition, the expression of CTR1 and FDX1 in the tubular epithelial cells in the H/R model and cell death reduced significantly after siRNA knockdown of the FDX1 gene or copper chelation therapy with tetrathiomolybdate. Preliminary mechanism investigation showed that the expression of CTR1 and FDX1 in H/R tubular epithelial cells and cell death was significantly reduced following siRNA knockdown of the steroidogenic factor 1 gene. Therefore, we speculate that copper-induced death in the RTECs may play an important role in the pathogenesis of AKI. Additionally, SF1 may be involved in the regulation of cuproptosis during AKI.