目标:虽然铜(Cu)对生物体至关重要,过量的铜可能是有害的。Ferroptosis是一种程序性细胞死亡途径,但是铁凋亡在铜诱导的肾损伤中的作用是有限的。本研究旨在探讨铁凋亡在鸡肾损伤中的作用及Cu促进肾铁凋亡的分子机制。
方法:通过在基础日粮中人工添加过量的Cu对鸡进行Cu处理(日粮中的Cu浓度补充至110-330mg/kg),以及对肾脏纤维化的影响,组织结构,并研究了与铁凋亡相关的分子标记。然后,铁死亡相关基因和蛋白质的表达水平,通过检测铁代谢和自噬,探讨铜对鸡肾脏铁凋亡的促进作用。
结果:Cu处理导致鸡肾脏明显的纤维化和组织结构损伤。分子分析显示LC3Ⅱ显著上调,P62,ATG5和NCOA4,以及FTH1和FTL蛋白水平的降低。此外,铁死亡的关键标志,包括GPX4,SLC7A11和FSP1的丢失,以及PTGS2和ACSL4蛋白水平的增加,在铜暴露后的鸡肾脏中观察到。
结论:我们的研究表明,膳食铜过量会导致肉鸡的肾损伤,并表现出与铁凋亡相关的特征,包括脂质过氧化,减少铁蛋白,以及FSP1和GPX4的下调。这些结果表明,过量的Cu可以诱导鸡的肾脏铁死亡并导致肾脏损伤。这项研究强调了铜离子与铁凋亡在肾损伤背景下的复杂相互作用,为理解铜诱导的肾损伤机制提供了新的视角。
OBJECTIVE: While copper (Cu) is essential for biological organisms, excessive Cu can be harmful. Ferroptosis is a programmed cell death pathway, but the role of ferroptosis in renal injury induced by Cu is limited. The aim of this study was to investigate the role of ferroptosis in kidney injury in chickens and the molecular mechanism by which Cu promotes renal ferroptosis.
METHODS: Chicken were subjected to Cu treatment by artificially adding excess Cu to the basal diet (the Cu concentration in the diet was supplemented to 110-330 mg/kg), and the impact on kidney fibrosis, tissue structure, and ferroptosis-related molecular markers was studied. Then, the expression levels of genes and proteins related to ferroptosis, iron metabolism and ferroautophagy were detected to explore the promoting effect of Cu on ferroptosis in chicken kidney.
RESULTS: Cu treatment resulted in significant fibrosis and tissue structure damage in chicken kidneys. Molecular analysis revealed a significant upregulation of LC3Ⅱ, P62, ATG5, and NCOA4, along with a decrease in FTH1 and FTL protein levels. Additionally, crucial markers of ferroptosis, including the loss of GPX4, SLC7A11, and FSP1, and an increase in PTGS2 and ACSL4 protein levels, were observed in chicken kidneys after Cu exposure.
CONCLUSIONS: Our study showed that dietary Cu excess caused kidney injury in brochickens and exhibited ferroptosis-related features, including lipid peroxidation, reduction of ferritin, and downregulation of FSP1 and GPX4. These results indicate that excess Cu can induce renal ferroptosis and lead to kidney injury in chickens. This study highlights the complex interplay between Cu ions and ferroptosis in the context of renal injury and provides a new perspective for understanding the mechanism of Cu-induced renal injury.