Life sciences · 2026
Nitroxyl relieves acute kidney injury by suppressing SLC31A1-mediated cuproptosis in renal tubular epithelial cells.
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Fu Xiao, Chen Bing-Xin, Wang Jing, Yang Le, Li Jiabao, Xu An-Jing, Wei Min, Feng Yu-Yan, Xing Hao-Yu, Fan Bo, Lin Shi-Bo, Zhu Xue-Xue, Bai Ning, Cao Cheng
Аннотация
CONTEXT: Cuproptosis, a copper-dependent form of programmed cell death, has been implicated in the pathogenesis of acute kidney injury (AKI). Nitroxyl (HNO), the one-electron reduced and protonated form of nitric oxide (NO), is an emerging regulator of cellular function. However, the role of HNO in modulating cuproptosis during AKI remains largely unexplored.
OBJECTIVE: This study aims to investigate the effect of HNO on cuproptosis in a murine model of renal ischemia-reperfusion (IR) injury.
MATERIALS AND METHODS: An in vitro hypoxia/reoxygenation (HR) model using human kidney-2 (HK-2) cells and an in vivo renal IR injury mouse model were employed to determine the role of HNO in renal function.
RESULTS: Here, we showed that baseline HNO fluorescence in HK-2 cells was enhanced by the HNO donor Angeli's salt (AS) and by the combined treatment with the hydrogen sulfide (H2S) donor NaHS and the nitric oxide (NO) donor SNP. In contrast, HR exposure significantly reduced HNO fluorescence. AS administration mitigated oxidative stress, decreased cell apoptosis, and reduced inflammation, along with an overall improvement in renal function in mice with renal IR injury. Pretreatment with AS significantly reduced HR-induced cell vitality injury, apoptosis, reactive oxygen species (ROS) formation, and mitochondrial dysfunction in HK-2 cells. HNO reduced cuproptosis by downregulating the protein expression of ferredoxin 1 (FDX1) and lipoyl synthase (LIAS), and suppressing copper accumulation. The copper ion carrier Elesclomol abolished the renal benefits of HNO. Mechanistic studies showed that HNO promoted the lysosomal localization and degradation of the copper transporter solute carrier family 31 member 1 (SLC31A1), thereby alleviating cuproptosis in renal tubular epithelial cells. Importantly, overexpression of SLC31A1 prevented the effects of HNO on cellular injury and cuproptosis.
DISCUSSION AND CONCLUSION: In summary, the present study demonstrated that HNO promotes the autophagy-lysosomal degradation of SLC31A1, which in turn inhibits cuproptosis and effectively alleviates AKI. These results provide experimental support for the potential of HNO as a promising agent for AKI.
OBJECTIVE: This study aims to investigate the effect of HNO on cuproptosis in a murine model of renal ischemia-reperfusion (IR) injury.
MATERIALS AND METHODS: An in vitro hypoxia/reoxygenation (HR) model using human kidney-2 (HK-2) cells and an in vivo renal IR injury mouse model were employed to determine the role of HNO in renal function.
RESULTS: Here, we showed that baseline HNO fluorescence in HK-2 cells was enhanced by the HNO donor Angeli's salt (AS) and by the combined treatment with the hydrogen sulfide (H2S) donor NaHS and the nitric oxide (NO) donor SNP. In contrast, HR exposure significantly reduced HNO fluorescence. AS administration mitigated oxidative stress, decreased cell apoptosis, and reduced inflammation, along with an overall improvement in renal function in mice with renal IR injury. Pretreatment with AS significantly reduced HR-induced cell vitality injury, apoptosis, reactive oxygen species (ROS) formation, and mitochondrial dysfunction in HK-2 cells. HNO reduced cuproptosis by downregulating the protein expression of ferredoxin 1 (FDX1) and lipoyl synthase (LIAS), and suppressing copper accumulation. The copper ion carrier Elesclomol abolished the renal benefits of HNO. Mechanistic studies showed that HNO promoted the lysosomal localization and degradation of the copper transporter solute carrier family 31 member 1 (SLC31A1), thereby alleviating cuproptosis in renal tubular epithelial cells. Importantly, overexpression of SLC31A1 prevented the effects of HNO on cellular injury and cuproptosis.
DISCUSSION AND CONCLUSION: In summary, the present study demonstrated that HNO promotes the autophagy-lysosomal degradation of SLC31A1, which in turn inhibits cuproptosis and effectively alleviates AKI. These results provide experimental support for the potential of HNO as a promising agent for AKI.